Cyclic Sulfonamides as Sodium Channel Blockers

ABSTRACT

The present disclosure provides cyclic sulfonamides of Formula (I), and the pharmaceutically acceptable salts and solvates thereof, wherein R 1 , R 2 , R 3a , R 3b , and n are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of sodium channels. For example, compounds of the present disclosure are useful for treating pain.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of medicinal chemistry. The inventionprovides novel cyclic sulfonamides and the use of these compounds asblockers of voltage-gated sodium (Na⁺) channels.

2. Background Art

Voltage-gated sodium channels (VGSCs) are found in all excitable cells.Sodium channels are primarily responsible for generating the rapidupstroke of the action potential in neuronal cells of the centralnervous system (CNS) and peripheral nervous system (PNS). In this mannersodium channels are essential to the initiation and propagation ofelectrical signals in the nervous system. Proper function of sodiumchannels is therefore necessary for normal function of the neuron.Consequently, aberrant sodium channel function is thought to underlie avariety of medical disorders (See Hubner et al., Hum. Mol. Genet.11:2435-2445 (2002) for a general review of inherited ion channeldisorders) including epilepsy (Yogeeswari et al, Curr. Drug Target5:589-602 (2004)), arrhythmia (Noble, Proc. Natl. Acad. Sci. USA99:5755-5756 (2002)), myotonia (Cannon, Kidney Int. 57:772-779 (2000)),and pain (Wood et al., J. Neurobiol., 61:55-71 (2004)).

VGSCs are composed of one α-subunit, which forms the core of the channeland is responsible for voltage-dependent gating and ion permeation, andseveral auxiliary β-subunits (see, e.g., Chahine et al., CNS &Neurological Disorders-Drug Targets 7:144-158 (2008) and Kyle and Ilyin,J. Med. Chem. 50:2583-2588 (2007)). α-Subunits are large proteinscomposed of four homologous domains. Each domain contains six α-helicaltransmembrane spanning segments. There are currently nine known membersof the family of voltage-gated sodium channel α-subunits. Names for thisfamily include SCNx, SCNAx, and Na_(v)x.x (see Table 1, below). The VGSCfamily has been phylogenetically divided into two subfamilies Na_(v)1.x(all but SCN6A) and Na_(v)2.x (SCN6A). The Na_(v)1.x subfamily can befunctionally subdivided into two groups, those which are sensitive toblocking by tetrodotoxin (TTX-sensitive or TTX-s) and those which areresistant to blocking by tetrodotoxin (TTX-resistant or TTX-r).

There are three members of the subgroup of TTX-resistant sodiumchannels. The SCN5A gene product (Na_(v)1.5, HI) is almost exclusivelyexpressed in cardiac tissue and has been shown to underlie a variety ofcardiac arrhythmias and other conduction disorders (Liu et al., Am. J.Pharmacogenomics 3:173-179 (2003)). Consequently, blockers of Na_(v)1.5have found clinical utility in treatment of such disorders (Srivatsa etal., Curr. Cardiol. Rep. 4:401-410 (2002)). The remaining TTX-resistantsodium channels, Na_(v)1.8 (SCN10A, PN3, SNS) and Na_(v)1.9 (SCN11A,NaN, SNS2) are expressed in the peripheral nervous system and showpreferential expression in primary nociceptive neurons. Human geneticvariants of these channels have not been associated with any inheritedclinical disorder. However, aberrant expression of Na_(v)1.8 has beenfound in the CNS of human multiple sclerosis (MS) patients and also in arodent model of MS (Black et al., Proc. Natl. Acad. Sci. USA97:11598-115602 (2000)). Evidence for involvement in nociception is bothassociative (preferential expression in nociceptive neurons) and direct(genetic knockout). Na_(v)1.8-null mice exhibited typical nociceptivebehavior in response to acute noxious stimulation but had significantdeficits in referred pain and hyperalgesia (Laird et al., J. Neurosci.22:8352-8356 (2002)).

TABLE 1 Voltage-gated sodium channel gene family Gene Tissue TTX IC₅₀Disease Type Symbol Distribution (nM) Association Indications Na_(v)1.1SCN1A CNS/PNS 10 Epilepsy Pain, seizures, neurodegeneration Na_(v)1.2SCN2A CNS 10 Epilepsy Epilepsy, neurodegeneration Na_(v)1.3 SCN3A CNS 15— Pain Na_(v)1.4 SCN4A Skeletal muscle 25 Myotonia Myotonia Na_(v)1.5SCN5A Heart muscle 2,000 Arrhythmia Arrhythmia Na_(v)1.6 SCN8A CNS/PNS 6— Pain, movement disorders Na_(v)1.7 SCN9A PNS 25 Erythermalgia PainNa_(v)1.8 SCN10A PNS 50,000 — Pain Na_(v)1.9 SCN11A PNS 1,000 — Pain

The Na_(v)1.7 (PN1, SCN9A) VGSC is sensitive to blocking by tetrodotoxinand is preferentially expressed in peripheral sympathetic and sensoryneurons. The SCN9A gene has been cloned from a number of species,including human, rat, and rabbit and shows ˜90% amino acid identitybetween the human and rat genes (Toledo-Aral et al., Proc. Natl. Acad.Sci. USA 94:1527-1532 (1997)).

An increasing body of evidence suggests that Na_(v)1.7 plays a key rolein various pain states, including acute, inflammatory and/or neuropathicpain. Deletion of the SCN9A gene in nociceptive neurons of mice led toan increase in mechanical and thermal pain thresholds and reduction orabolition of inflammatory pain responses (Nassar et al., Proc. Natl.Acad. Sci. USA 101:12706-12711 (2004)).

Sodium channel-blocking agents have been reported to be effective in thetreatment of various disease states, and have found particular use aslocal anesthetics, e.g., lidocaine and bupivacaine, and in the treatmentof cardiac arrhythmias, e.g., propafenone and amiodarone, and epilepsy,e.g., lamotrigine, phenytoin and carbamazepine (see Clare et al., DrugDiscovery Today 5:506-510 (2000); Lai et al., Annu. Rev. Pharmacol.Toxicol. 44:371-397 (2004); Anger et al., J. Med. Chem. 44:115-137(2001), and Catterall, Trends Pharmacol. Sci. 8:57-65 (1987)). Each ofthese agents is believed to act by interfering with the rapid influx ofsodium ions.

Other sodium channel blockers such as BW619C89 and lifarizine have beenshown to be neuroprotective in animal models of global and focalischemia (Graham et al., J. Pharmacol. Exp. Ther. 269:854-859 (1994);Brown et al., British J. Pharmacol. 115:1425-1432 (1995)).

It has also been reported that sodium channel-blocking agents can beuseful in the treatment of pain, including acute, chronic, inflammatory,neuropathic, and other types of pain such as rectal, ocular, andsubmandibular pain typically associated with paroxysmal extreme paindisorder; see, for example, Kyle and Ilyin., J. Med. Chem. 50:2583-2588(2007); Wood et al., J. Neurobiol. 61:55-71 (2004); Baker et al., TRENDSin Pharmacological Sciences 22:27-31 (2001); and Lai et al., CurrentOpinion in Neurobiology 13:291-297 (2003); the treatment of neurologicaldisorders such as epilepsy, seizures, epilepsy with febrile seizures,epilepsy with benign familial neonatal infantile seizures, inheritedpain disorders, e.g., primary erthermalgia and paroxysmal extreme paindisorder, familial hemiplegic migraine, and movement disorder; and thetreatment of other psychiatric disorders such as autism, cerebellaratrophy, ataxia, and mental retardation; see, for example, Chahine etal., CNS & Neurological Disorders-Drug Targets 7:144-158 (2008) andMeisler and Kearney, J. Clin. Invest. 115:2010-2017 (2005). In additionto the above-mentioned clinical uses, carbamazepine, lidocaine andphenytoin are used to treat neuropathic pain, such as from trigeminalneuralgia, diabetic neuropathy and other forms of nerve damage (Taylorand Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)). Furthermore,based on a number of similarities between chronic pain and tinnitus,(Moller, Am. J. Otol. 18:577-585 (1997); Tonndorf, Hear. Res. 28:271-275(1987)) it has been proposed that tinnitus should be viewed as a form ofchronic pain sensation (Simpson, et al., Tip. 20:12-18 (1999)). Indeed,lidocaine and carbamazepine have been shown to be efficacious intreating tinnitus (Majumdar, B. et al., Clin. Otolaryngol. 8:175-180(1983); Donaldson, Laryngol. Otol. 95:947-951 (1981)).

Many patients with either acute or chronic pain disorders respond poorlyto current pain therapies, and the development of resistance orinsensitivity to opiates is common. In addition, many of the currentlyavailable treatments have undesirable side effects.

In view of the limited efficacy and/or unacceptable side-effects of thecurrently available agents, there is a pressing need for more effectiveand safer analgesics that work by blocking sodium channels.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides cyclic sulfonamidesrepresented by Formula I, below, and the pharmaceutically acceptablesalts and solvates thereof, collectively referred to herein as“Compounds of the Invention.”

In another aspect, the present disclosure provides the use of Compoundsof the Invention as blockers of sodium (Na⁺) channels.

In another aspect, the present disclosure provides a method of treatinga disorder responsive to the blockade of sodium channels in a mammal,comprising administering to the mammal an effective amount of a Compoundof the Invention.

In another aspect, the present disclosure provides a method of treatingpain (e.g., acute pain, chronic pain, which includes but is not limitedto, neuropathic pain, postoperative pain, and inflammatory pain, orsurgical pain), comprising administering an effective amount of aCompound of the Invention to a mammal in need of such treatment.Specifically, the present disclosure provides a method for preemptive orpalliative treatment of pain by administering an effective amount of aCompound of the Invention to a mammal in need of such treatment.

In another aspect, the present disclosure provides a method of treatingstroke, neuronal damage resulting from head trauma, epilepsy, seizures,general epilepsy with febrile seizures, severe myoclonic epilepsy ininfancy, neuronal loss following global and focal ischemia, migraine,familial primary erythromelalgia, paroxysmal extreme pain disorder,cerebellar atrophy, ataxia, dystonia, tremor, mental retardation,autism, a neurodegenerative disorder (e.g., Alzheimer's disease,amyotrophic lateral sclerosis (ALS), or Parkinson's disease), manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia, comprising administering aneffective amount of a Compound of the Invention to a mammal in need ofsuch treatment.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a Compound of the Invention and one or morepharmaceutically acceptable carriers. The pharmaceutical compositions ofthe present invention may be formulated as immediate releaseformulations, or as controlled or sustained release formulations.

In another aspect, the present disclosure provides a pharmaceuticalcomposition capable of treating a disorder responsive to the blockade ofsodium ion channels, wherein the pharmaceutical composition comprises aneffective amount of a Compound of the Invention in a mixture with one ormore pharmaceutically acceptable carriers.

In another aspect, the present disclosure provides a method ofmodulating sodium channels in a mammal, comprising administering to themammal an effective amount of at least one Compound of the Invention.

In another aspect, the present disclosure provides Compounds of theInvention for use in treating pain in a mammal, e.g., acute pain,chronic pain (which includes but is not limited to, neuropathic pain,postoperative pain, and inflammatory pain), or surgical pain.

In another aspect, the present disclosure provides Compounds of theInvention for use in treating stroke, neuronal damage resulting fromhead trauma, epilepsy, seizures, general epilepsy with febrile seizures,severe myoclonic epilepsy in infancy, neuronal loss following global andfocal ischemia, migraine, familial primary erythromelalgia, paroxysmalextreme pain disorder, cerebellar atrophy, ataxia, dystonia, tremor,mental retardation, autism, a neurodegenerative disorder (e.g.,Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or Parkinson'sdisease), manic depression, tinnitus, myotonia, a movement disorder, orcardiac arrhythmia, or providing local anesthesia, in a mammal.

In another aspect, the present disclosure provides radiolabeledCompounds of the Invention and the use of such compounds as radioligandsin any appropriately selected competitive binding assays and screeningmethodologies. Thus, the present disclosure further provides a methodfor screening a candidate compound for its ability to bind to a sodiumchannel or sodium channel subunit using a radiolabeled Compound of theInvention. In certain embodiments, the compound is radiolabeled with ³H,¹¹C, or ¹⁴C. This competitive binding assay can be conducted using anyappropriately selected methodology. In one embodiment, the screeningmethod comprises: i) introducing a fixed concentration of theradiolabeled compound to an in vitro preparation comprising a soluble ormembrane-associated sodium channel, subunit or fragment under conditionsthat permit the radiolabeled compound to bind to the channel, subunit orfragment, respectively, to form a conjugate; ii) titrating the conjugatewith a candidate compound; and iii) determining the ability of thecandidate compound to displace the radiolabeled compound from saidchannel, subunit or fragment.

In another aspect, the present disclosure provides a Compound of theInvention for use in the manufacture of a medicament for treating painin a mammal. In one embodiment, the present disclosure provides the useof a Compound of the Invention in the manufacture of a medicament forpalliative or preemptive treatment of pain, such as acute pain, chronicpain, or surgical pain.

In another aspect, the present disclosure provides a Compound of theInvention for use in the manufacture of a medicament for treatingstroke, neuronal damage resulting from head trauma, epilepsy, seizures,general epilepsy with febrile seizures, severe myoclonic epilepsy ininfancy, neuronal loss following global and focal ischemia, migraine,familial primary erythromelalgia, paroxysmal extreme pain disorder,cerebellar atrophy, ataxia, dystonia, tremor, mental retardation,autism, a neurodegenerative disorder (e.g., Alzheimer's disease,amyotrophic lateral sclerosis (ALS), or Parkinson's disease), manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia, in a mammal.

The invention still further relates to a kit comprising a container(preferably sterile) containing an effective amount of a Compound of theInvention.

Additional embodiments and advantages of the disclosure will be setforth, in part, in the description that follows, and will flow from thedescription, or can be learned by practice of the disclosure. Theembodiments and advantages of the disclosure will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only, and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present disclosure is based on the use of Compounds ofthe Invention as blockers of Na⁺ channels. In view of this property,Compounds of the Invention are useful for treating disorders responsiveto the blockade of sodium ion channels.

In one embodiment, Compounds of the Invention are compounds representedby Formula I:

and the pharmaceutically acceptable salts and solvates thereof,wherein:

R¹ is optionally substituted 5-membered heteroaryl;

R² is selected from the group consisting of:

R^(3a) and R^(3b) are each independently selected from the groupconsisting of hydrogen and halogen;

R^(4a), R^(4b), R^(4d), and R^(4e) are each independently selected fromthe group consisting of hydrogen, alkyl, halo, nitro, cyano, hydroxy,amino, alkylamino, dialkylamino, haloalkyl, monohydroxyalkyl,dihydroxyalkyl, alkoxy, haloalkoxy, carboxy, and alkoxycarbonyl;

R^(4c) is selected from the group consisting of aryloxy andheteroaryloxy;

R^(5a) is selected from the group consisting of optionally substitutedaryl and optionally substituted heteroaryl;

R^(5b), R^(5C), R^(5d), and R^(5e) are each independently selected fromthe group consisting of hydrogen, alkyl, halo, nitro, cyano, hydroxy,amino, alkylamino, dialkylamino, haloalkyl, monohydroxyalkyl,dihydroxyalkyl, alkoxy, haloalkoxy, carboxy, and alkoxycarbonyl;

R^(6a), R^(6b), R^(6c), and R^(6d) are each independently selected fromthe group consisting of hydrogen, alkyl, halo, nitro, cyano, hydroxy,amino, alkylamino, dialkylamino, haloalkyl, monohydroxyalkyl,dihydroxyalkyl, alkoxy, haloalkoxy, carboxy, and alkoxycarbonyl; and

n is 1, 2, or 3.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R^(3a) and R^(3b) are hydrogen, and R¹, R² andn are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein n is 1, and R¹, R², R^(3a) and R^(3b) are asdefined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein n is 2, and R¹, R², R^(3a) and R^(3b) are asdefined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R¹ is selected from the group consisting2-furyl, 3-furyl, thien-2-yl, thien-3-yl, oxazol-2-yl, oxazol-4-yl,oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 1H-pyrazol-3-yl,1H-pyrazol-4-yl, 1H-pyrazol-5-yl, isoxazol-3-yl, isoxazol-4-yl,isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,3oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl, 1,2,3 triazol-4-yl, 1,2,3-triazol-5-yl,1,3,4-oxadiazolyl, and 1,3,4-thiadiazolyl, any of which is optionallysubstituted, and R², R^(3a), R^(3b), and n are as defined above inconnection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R¹ is selected from the group consisting ofoptionally substituted thiazol-2-yl and optionally substituted1,3,4-thiadiazolyl, and R², R^(3a), R^(3b), and n are as defined abovein connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R¹ is optionally substituted thiazol-2-yl, andR², R^(3a), R^(3b), and n are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R′ is thiazol-2-yl, and R², R^(3a), R^(3b),and n are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R² is:

and R¹, R^(3a), R^(3b), and n are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R² is:

R^(4c) is heteroaryloxy; R^(4a), R^(4b), R^(4d), and R^(4e) are eachindependently selected from the group consisting of hydrogen and halo,and R¹, R^(3a), R^(3b), and n are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R² is:

R^(4c) is aryloxy; R^(4a), R^(4b), R^(4d) and R^(4e) are eachindependently selected from the group consisting of hydrogen and halo,and R¹, R^(3a), R^(3b), and n are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R² is:

andR^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each independentlyselected from the group consisting of hydrogen, alkyl, halo, nitro,cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, carboxy, andalkoxycarbonyl, and R¹, R^(3a), R^(3b), and n are as defined above inconnection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R² is:

and R¹, R^(3a), R^(3b), R^(5a), R^(5b), R^(5c), R^(5d), R^(5e) and n areas defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R² is:

andR^(5b), R^(5c), R^(5d), and R^(5e) are each independently selected fromthe group consisting of hydrogen, alkyl, halo, cyano, hydroxy, alkoxy,and haloalkoxy, and R¹, R^(3a), R^(3b), and n are as defined above inconnection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R² is:

R^(5b), R^(5c), R^(5d), and R^(5e) are each independently selected fromthe group consisting of hydrogen, alkyl, halo, cyano, hydroxy, alkoxy,and haloalkoxy; and R^(5a) is optionally substituted phenyl, and R¹,R^(3a), R^(3b), and n are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R² is:

R^(5b), R^(5c), R^(5d), and R^(5e) are each independently selected fromthe group consisting of hydrogen, alkyl, halo, cyano, hydroxy, alkoxy,and haloalkoxy; and R^(5a) is optionally substituted heteroaryl, and R¹,R^(3a), R^(3b), and n are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R² is:

and R¹, R^(3a), R^(3b), R^(6a), R^(6b), R^(6c), R^(6d) and n are asdefined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R² is:

and

R^(6a), R^(6b), R^(6c), and R^(6d) are each hydrogen, and R¹, R^(3a),R^(3b), and n are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compounds of TABLE2, and the pharmaceutically acceptable salts and solvates thereof.

TABLE 2 Compound Example No. Structure 1

2

3

4

5

6

7

The chemical names of the compound examples are provided in TABLE 3.

TABLE 3 Compound Example No. Chemical Name 15-(2-(pyridazin-4-yl)-4-(trifluoromethyl)phenoxy)-2-(thiazol-2-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide 25-([1,1′-biphenyl]-2-yloxy)-2-(thiazol-2-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide 35-(4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)-2-(thiazol-2-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide 45-(3H-spiro[isobenzofuran-1,4′-piperidin]-1′-yl)-2-(thiazol-2-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide 56-(3H-spiro[isobenzofuran-1,4′-piperidin]-1′-yl)-2-(thiazol-2-yl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide 66-([1,1′-biphenyl]-2-yloxy)-2-(thiazol-2-yl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide 72-(thiazol-2-yl)-6-(4-(4-(trifluoromethyl)phenoxy)phenyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide

In another embodiment, the present disclosure provides a pharmaceuticalcomposition comprising a Compound of the Invention and apharmaceutically acceptable carrier.

In another embodiment, the present disclosure provides a method oftreating a disorder responsive to the blockade of sodium channels in amammal suffering from said disorder, comprising administering to amammal in need of such treatment an effective amount of a Compound ofthe Invention.

In another embodiment, the present disclosure provides a method oftreating a disorder responsive to the blockade of TTX-resistant sodiumchannels in a mammal suffering from said disorder, comprisingadministering to a mammal in need of such treatment an effective amountof a Compound of the Invention.

In another embodiment, the present disclosure provides a method oftreating a disorder responsive to the blockade of TTX-sensitive sodiumchannels in a mammal suffering from said disorder, comprisingadministering to a mammal in need of such treatment an effective amountof a Compound of the Invention.

In another embodiment, the present disclosure provides a method oftreating a disorder responsive to the blockade of Na_(v)1.7 sodiumchannels in a mammal suffering from said disorder, comprisingadministering to a mammal in need of such treatment an effective amountof a Compound of the Invention.

In another embodiment, the present disclosure provides a method oftreating stroke, neuronal damage resulting from head trauma, epilepsy,seizures, neuronal loss following global and focal ischemia, pain,migraine, primary erythromelalgia, paroxysmal extreme pain disorder,cerebellar atrophy, ataxia, mental retardation, a neurodegenerativedisorder, manic depression, tinnitus, myotonia, a movement disorder, orcardiac arrhythmia, or providing local anesthesia in a mammal,comprising administering to a mammal in need of such treatment aneffective amount of a Compound of the Invention.

In another embodiment, the present disclosure provides a method fortreating pain, comprising administering to a mammal in need of suchtreatment an effective amount of a Compound of the Invention.

In another embodiment, the present disclosure provides a method for thepreemptive or palliative treatment of pain, comprising administering toa mammal in need of such treatment an effective amount of a Compound ofthe Invention.

In another embodiment, the present disclosure provides a method oftreating chronic pain, inflammatory pain, neuropathic pain, acute pain,and surgical pain, comprising administering to a mammal in need of suchtreatment an effective amount of a Compound of the Invention.

In another embodiment, the present disclosure provides a method ofmodulating sodium channels, e.g., Na_(v)1.7 sodium channels, in amammal, comprising administering to the mammal in need of suchmodulation at least one Compound of the Invention.

In another embodiment, the present disclosure provides a pharmaceuticalcomposition, comprising a Compound of the Invention useful for treatinga disorder responsive to the blockade of sodium ion channels such aspain.

In another embodiment, the present disclosure provides a Compound of theInvention for use in treating a disorder responsive to the blockade ofsodium ion channels such as pain.

In another embodiment, the present disclosure provides a Compound of theInvention wherein said compound is ³H, ¹¹C, or ¹⁴C radiolabeled.

In another embodiment, the present disclosure provides a method ofscreening a candidate compound for the ability to bind to a binding siteon a protein using a radiolabeled Compound of the Invention, comprising:

a) introducing a fixed concentration of said radiolabeled compound to anin vitro preparation comprising a soluble or membrane-associated sodiumchannel, subunit or fragment thereof under conditions that permit saidradiolabeled compound to bind to said channel, subunit or fragment,respectively, to form a conjugate;

b) titrating said conjugate with said candidate compound; and

c) determining the ability of said candidate compound to displace saidradiolabeled Compound of the Invention from said channel, subunit orfragment.

In another embodiment, the present disclosure provides a method ofpreparing a pharmaceutical composition, comprising admixing atherapeutically effective amount of a Compound of the Invention with apharmaceutically acceptable carrier.

In another embodiment, the present disclosure provides the use of aCompound of the Invention in the manufacture of a medicament fortreating or preventing stroke, neuronal damage resulting from headtrauma, epilepsy, seizures, neuronal loss following global and focalischemia, pain, migraine, primary erythromelalgia, paroxysmal extremepain disorder, cerebellar atrophy, ataxia, mental retardation, aneurodegenerative disorder, manic depression, tinnitus, myotonia, amovement disorder, or cardiac arrhythmia, or providing local anesthesia.

In another embodiment, the present disclosure provides the use of aCompound of the Invention in the manufacture of a medicament fortreating pain.

In another embodiment, the present disclosure provides a Compound of theInvention for use in the treatment or prevention of stroke, neuronaldamage resulting from head trauma, epilepsy, seizures, neuronal lossfollowing global and focal ischemia, pain, migraine, primaryerythromelalgia, paroxysmal extreme pain disorder, cerebellar atrophy,ataxia, mental retardation, a neurodegenerative disorder, manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia.

In another embodiment, the present disclosure provides a Compound of theInvention for use in the treatment or prevention of pain.

For the purpose of the present disclosure, the term “alkyl” as used byitself or as part of another group refers to a straight- orbranched-chain aliphatic hydrocarbon containing 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, or 12 carbon atoms (i.e., C₁₋₁₂ alkyl) or the number ofcarbon atoms designated (i.e., a C₁ alkyl such as methyl, a C₂ alkylsuch as ethyl, a C₃ alkyl such as propyl or isopropyl, etc.). In oneembodiment, the alkyl group is chosen from a straight chain C₁₋₁₀ alkylgroup. In another embodiment, the alkyl group is chosen from a branchedchain C₃₋₁₀ alkyl group. In another embodiment, the alkyl group ischosen from a straight chain C₁₋₆ alkyl group. In another embodiment,the alkyl group is chosen from a branched chain C₃₋₆ alkyl group. Inanother embodiment, the alkyl group is chosen from a straight chain C₁₋₄alkyl group. In another embodiment, the alkyl group is chosen from abranched chain C₁₋₄ alkyl group. In another embodiment, the alkyl groupis chosen from a straight or branched chain C₃₋₆ alkyl group. In anotherembodiment, the alkyl group is chosen from a straight or branched chainC₂₋₄ alkyl group. Non-limiting exemplary C₁₋₁₀ alkyl groups includemethyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, and n-decyl, isopropyl, sec-butyl, tert-butyl, iso-butyl,iso-pentyl, neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl,1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl,1,3-dimethylheptyl, and 3,3-dimethylheptyl. Non-limiting exemplary C₁₋₄alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, and iso-butyl.

For the purpose of the present disclosure, the term “optionallysubstituted alkyl” as used by itself or as part of another group meansthat the alkyl as defined above is either unsubstituted or substitutedwith one, two, or three substituents independently chosen from nitro,haloalkoxy, aryl oxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl,aryl carbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, andcycloalkyl. In one embodiment, the optionally substituted alkyl issubstituted with two substituents. In another embodiment, the optionallysubstituted alkyl is substituted with one substituent. Non-limitingexemplary optionally substituted alkyl groups include —CH₂CH₂NO₂,—CH₂CH₂CO₂H, —CH₂CH₂SO₂CH₃, —CH₂CH₂COPh, and —CH₂C₆H₁₁.

For the purpose of the present disclosure, the term “cycloalkyl” as usedby itself or as part of another group refers to saturated and partiallyunsaturated (containing e.g. one or two double bonds) cyclic aliphatichydrocarbons containing one, two or three rings having 3, 4, 5, 6, 7, 8,9, 10, 11, or 12 carbon atoms (i.e., C₃₋₁₂ cycloalkyl) or the number ofcarbons designated. In one embodiment, the cycloalkyl group has tworings. In another embodiment, the cycloalkyl group has one ring. Inanother embodiment, the cycloalkyl group is chosen from a C₃₋₈cycloalkyl group. In another embodiment, the cycloalkyl group is chosenfrom a C₃₋₆ cycloalkyl group. Non-limiting exemplary cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl,norbornyl, decalin, adamantyl, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl,cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl,cyclononadienyl, cyclononatrienyl, cyclodecenyl, cyclodecadienyl,cyclotetradecenyl, and cyclododecadienyl.

For the purpose of the present disclosure, the term “optionallysubstituted cycloalkyl” as used by itself or as part of another groupmeans that the cycloalkyl as defined above is either unsubstituted orsubstituted with one, two, or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy,aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,(alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and(heteroaryl)alkyl. In one embodiment, the optionally substitutedcycloalkyl is substituted with two substituents. In another embodiment,the optionally substituted cycloalkyl is substituted with onesubstituent. Non-limiting exemplary optionally substituted cycloalkylgroups include:

For the purpose of the present disclosure, the term “alkenyl” as used byitself or as part of another group refers to an alkyl group having 2, 3,4, 5, 6, 7, 8, 9, or 10 carbon atoms (C₂₋₁₀alkenyl) and including atleast one, e.g. one, two or three, carbon-carbon double bond. In oneembodiment, the alkenyl group is chosen from a C₂₋₆ alkenyl group. Inanother embodiment, the alkenyl group is chosen from a C₂₋₄ alkenylgroup. Non-limiting exemplary alkenyl groups include ethenyl, propenyl,isopropenyl, butenyl, sec-butenyl, iso-butylenyl, 1-pentenyl,2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl,2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl,2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl,2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, and the like.

For the purpose of the present disclosure, the term “optionallysubstituted alkenyl” as used herein by itself or as part of anothergroup means the alkenyl as defined above is either unsubstituted orsubstituted with one, two or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy,aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, orheterocyclo.

For the purpose of the present disclosure, the term “alkynyl” as used byitself or as part of another group refers to an alkyl group having 2, 3,4, 5, 6, 7, 8, 9, or 10 carbon atoms ((C₂₋₁₀)alkynyl) and including atleast one, e.g. one, two or three, carbon-carbon triple bond. In oneembodiment, the alkynyl has one carbon-to-carbon triple bond. In anotherembodiment, the alkynyl group is chosen from a C₂₋₆ alkynyl group. Inanother embodiment, the alkynyl group is chosen from a C₂₋₄ alkynylgroup. Non-limiting exemplary alkynyl groups include ethynyl, propynyl,1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl,6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl,8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl, and the like.

For the purpose of the present disclosure, the term “optionallysubstituted alkynyl” as used herein by itself or as part of anothergroup means the alkynyl as defined above is either unsubstituted orsubstituted with one, two or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy,aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, aryl sulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, orheterocyclo.

For the purpose of the present disclosure, the term “haloalkyl” as usedby itself or as part of another group refers to an alkyl groupsubstituted by one or more fluorine, chlorine, bromine and/or iodineatoms. In one embodiment, the alkyl group is substituted by one, two, orthree fluorine and/or chlorine atoms. In another embodiment, thehaloalkyl group is chosen from a C₁₋₄ haloalkyl group. Non-limitingexemplary haloalkyl groups include fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, andtrichloromethyl groups.

For the purpose of the present disclosure, the term “monohydroxyalkyl”as used by itself or as part of another group refers to an alkyl groupas defined above substituted with exactly one hydroxy group.Non-limiting exemplary monohydroxyalkyl groups include hydroxymethyl,hydroxyethyl, hydroxypropyl and hydroxybutyl groups. In one embodiment,the monohydroxyalkyl group is a C₁₋₆ monohydroxyalkyl. In anotherembodiment, the monohydroxyalkyl group is a C₁₋₄ monohydroxyalkyl.

For the purpose of the present disclosure, the term “dihydroxyalkyl” asused by itself or as part of another group refers to an alkyl group asdefined above substituted with exactly two hydroxy groups. Non-limitingexemplary dihydroxyalkyl groups include 1,2-dihydroxyethyl and1,3-dihydroxyprop-2-yl. In one embodiment, the dihydroxyalkyl group is aC₂₋₆ dihydroxyalkyl. In another embodiment, the dihydroxyalkyl group isa C₂₋₄ dihydroxyalkyl. In another embodiment, the dihydroxyalkyl groupis a C₂ dihydroxyalkyl.

For the purpose of the present disclosure, the term “alkoxy” as used byitself or as part of another group refers to an optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substituted alkenylor optionally substituted alkynyl attached to a terminal oxygen atom. Inone embodiment, the alkoxy group is chosen from a C₁₋₆ alkoxy group. Inanother embodiment, the alkoxy group is chosen from a C₁₋₄ alkylattached to a terminal oxygen atom, e.g., methoxy, ethoxy, andtert-butoxy.

For the purpose of the present disclosure, the term “alkylthio” as usedby itself or as part of another group refers to a sulfur atomsubstituted by an optionally substituted alkyl group. In one embodiment,the alkylthio group is chosen from a C₁₋₄ alkylthio group. Non-limitingexemplary alkylthio groups include —SCH₃, and —SCH₂CH₃.

For the purpose of the present disclosure, the term “alkoxyalkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with an alkoxy group. Non-limiting exemplary alkoxyalkylgroups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl,ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl,iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl,tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, andpentyloxymethyl.

For the purpose of the present disclosure, the term “heteroalkyl” asused by itself or part of another group refers to a stable straight orbranched chain hydrocarbon radical containing 1, 2, 3, 4, 5, 6, 7, 8, 9,or 10 carbon atoms and 1 or 2 heteroatoms, which can be the same ordifferent, selected from O, N, or S, wherein: 1) the nitrogen atom(s)and sulfur atom(s) can optionally be oxidized (to yield an N-oxide,sulfoxide or sulfone); and/or 2) the nitrogen atom(s) can optionally bequaternized. The heteroatoms can be placed at any interior position ofthe heteroalkyl group or at a position at which the heteroalkyl group isattached to the remainder of the molecule. In one embodiment, theheteroalkyl group contains two oxygen atoms. Non-limiting exemplaryheteroalkyl groups include —CH₂OCH₂CH₂OCH₃, —OCH₂CH₂OCH₂CH₂OCH₃,—CH₂NHCH₂CH₂OCH₂, —OCH₂CH₂NH₂, and —NHCH₂CH₂N(H)CH₃.

For the purpose of the present disclosure, the term “haloalkoxy” as usedby itself or as part of another group refers to a haloalkyl attached toa terminal oxygen atom. Non-limiting exemplary haloalkoxy groups includefluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, and2,2,2-trifluoroethoxy.

For the purpose of the present disclosure, the term “aryl” as used byitself or as part of another group refers to a monocyclic or bicyclicaromatic ring system having from six to fourteen carbon atoms (i.e.,C₆₋₁₄ aryl). Non-limiting exemplary aryl groups include phenyl(abbreviated as “Ph”), naphthyl, phenanthryl, anthracyl, indenyl,azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In oneembodiment, the aryl group is chosen from phenyl or naphthyl.

For the purpose of the present disclosure, the term “optionallysubstituted aryl” as used herein by itself or as part of another groupmeans that the aryl as defined above is either unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents independently chosen fromhalo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy,aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,(alkylamino)alkyl, (dial kylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, or(heteroaryl)alkyl. In one embodiment, the optionally substituted aryl isan optionally substituted phenyl. In another embodiment, the optionallysubstituted phenyl has four substituents. In another embodiment, theoptionally substituted phenyl has three substituents. In anotherembodiment, the optionally substituted phenyl has two substituents. Inanother embodiment, the optionally substituted phenyl has onesubstituent. Non-limiting exemplary substituted aryl groups include2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-cyanophenyl, 3-methylphenyl, 3-methoxyphenyl,3-fluorophenyl, 3-chlorophenyl, 3-cyanophenyl, 4-methylphenyl,4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl,4-cyanophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl,3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl,3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl,2-fluoro-3-chlorophenyl, 2-trifluoromethyl-4-cyanophenyl,2-fluoro-5-chlorophenyl, 2-fluoro-5-chlorophenyl,2-fluoro-4-chlorophenyl, 2-cyano-3-trifluorophenyl and3-chloro-4-fluorophenyl. The term optionally substituted aryl is meantto include groups having fused optionally substituted cycloalkyl andfused optionally substituted heterocyclo rings. Examples include:

For the purpose of the present disclosure, the term “aryloxy” as used byitself or as part of another group refers to an optionally substitutedaryl attached to a terminal oxygen atom. Non-limiting exemplary aryloxygroups include:

For the purpose of the present disclosure, the term “heteroaryloxy” asused by itself or as part of another group refers to an optionallysubstituted heteroaryl attached to a terminal oxygen atom. Non-limitingexemplary heteroaryloxy groups include:

For the purpose of the present disclosure, the term “aralkyloxy” as usedby itself or as part of another group refers to an aralkyl groupattached to a terminal oxygen atom. A non-limiting exemplary aralkyloxygroup is benzyloxy (PhCH₂O—).

For the purpose of the present disclosure, the term “heteroaryl” or“heteroaromatic” refers to monocyclic and bicyclic aromatic ring systemshaving 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms (i.e., C₅₋₁₄heteroaryl or 5- to 14-membered heteroaryl) and 1, 2, 3, or 4heteroatoms independently chosen from oxygen, nitrogen and sulfur. Inone embodiment, the heteroaryl has three heteroatoms. In anotherembodiment, the heteroaryl has two heteroatoms. In another embodiment,the heteroaryl has one heteroatom. In another embodiment, the heteroarylis a C₅ heteroaryl. In another embodiment, the heteroaryl is a C₆heteroaryl. Non-limiting exemplary heteroaryl groups include thienyl,benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl,pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl,2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl,purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl,furazanyl, and phenoxazinyl. In another embodiment, the heteroaryl ischosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g.,2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl,and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, andpyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl,thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl,isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl,oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl,isoxazol-4-yl, and isoxazol-5-yl). The term “heteroaryl” is also meantto include possible N-oxides. Non-limiting exemplary N-oxides includepyridyl N-oxide.

For the purpose of the present disclosure, the term “optionallysubstituted heteroaryl” as used by itself or as part of another groupmeans that the heteroaryl as defined above is either unsubstituted orsubstituted with 1, 2, 3, or 4 substituents, e.g., one or twosubstituents, independently chosen from halo, nitro, cyano, hydroxy,amino, alkylamino, dialkylamino, haloalkyl, monohydroxyalkyl,dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio,carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl,(heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, theoptionally substituted heteroaryl has one substituent. In anotherembodiment, the optionally substituted heteroaryl is an optionallysubstituted pyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon ornitrogen atom can be substituted. In another embodiment, the optionallysubstituted heteroaryl is an optionally substituted indole.

For the purpose of the present disclosure, the term “heterocyclo” asused by itself or as part of another group refers to saturated andpartially unsaturated (e.g., containing one or two double bonds) cyclicgroups containing 1, 2, or 3 rings having from 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, or 14 carbon atoms (i.e., C₂₋₁₄ heterocyclo) and one ortwo oxygen, sulfur and/or nitrogen atoms. The term “heterocyclo” ismeant to include cyclic ureido groups such as 2-imidazolidinone andcyclic amide groups such as β-lactam, γ-lactam, δ-lactam and ε-lactam.The term “heterocyclo” is also meant to include groups having fusedoptionally substituted aryl groups, e.g., indolinyl. In one embodiment,the heterocyclo group is chosen from a 5- or 6-membered cyclic groupcontaining one ring and one or two oxygen and/or nitrogen atoms. Theheterocyclo can be optionally linked to the rest of the molecule througha carbon or nitrogen atom. In another embodiment the “heterocyclo” is a3- to 8-membered heterocyclo. Non-limiting exemplary heterocyclo, i.e.3- to 8-membered heterocyclo, groups include 2-imidazolidinone,piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and indolinyl.

For the purpose of the present disclosure, the term “optionallysubstituted heterocyclo” as used herein by itself or part of anothergroup means the heterocyclo as defined above is either unsubstituted orsubstituted with one to four substituents independently selected fromhalo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy,aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,(alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and(heteroaryl)alkyl. Substitution may occur on any available carbon ornitrogen atom. Non-limiting exemplary optionally substituted heterocyclogroups include:

For the purpose of the present disclosure, the term “amino” as used byitself or as part of another group refers to —NH₂.

For the purpose of the present disclosure, the term “alkylamino” as usedby itself or as part of another group refers to —NHR¹³, wherein R¹³ isalkyl.

For the purpose of the present disclosure, the term “dialkylamino” asused by itself or as part of another group refers to —NR^(14a)R^(14b),wherein R^(14a) and R^(14b) are each independently alkyl or R^(14a) andR^(14b) are taken together to form a 3- to 8-membered optionallysubstituted heterocyclo.

For the purpose of the present disclosure, the term “hydroxyalkylamino”as used by itself or as part of another group refers to —NHR¹⁵, whereinR¹⁵ is monohydroxyalkyl or dihydroxyalkyl.

For the purpose of the present disclosure, the term “arylamino” as usedby itself or as part of another group refers to —NR^(16a)R^(16b),wherein R^(16a) is optionally substituted aryl and R^(16b) is hydrogenor alkyl.

For the purpose of the present disclosure, the term “cycloalkylamino” asused by itself or as part of another group refers to —NR^(17a)R^(17b),wherein R^(17a) is optionally substituted cycloalkyl and R^(17b) ishydrogen or alkyl.

For the purpose of the present disclosure, the term “heteroarylamino” asused by itself or as part of another group refers to —NR^(18a)R^(18b)wherein R^(18a) is optionally substituted heteroaryl and R^(18b) ishydrogen or alkyl.

For the purpose of the present disclosure, the term “heterocycloamino”as used by itself or as part of another group refers to —NR^(19a)R^(19b)wherein R^(19a) is optionally substituted heterocyclo and R^(19b) ishydrogen or alkyl.

For the purpose of the present disclosure, the term “(amino)alkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with an amino group. Non-limiting exemplary amino alkylgroups include —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, and —CH₂CH₂CH₂CH₂NH₂.

For the purpose of the present disclosure, the term “diaminoalkyl” asused by itself or as part of another group refers an alkyl groupsubstituted with two amino groups. A non-limiting exemplary diaminoalkylincludes —CH₂CH(NH₂)CH₂CH₂NH₂.

For the purpose of the present disclosure, the term “(alkylamino)alkyl”as used by itself or as part of another group refers an alkyl groupsubstituted with an alkylamino group. A non-limiting exemplary(alkylamino)alkyl group is —CH₂CH₂N(H)CH₃.

For the purpose of the present disclosure, the term“(dialkylamino)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted by a dialkylamino group. Anon-limiting exemplary (dialkylamino)alkyl group is —CH₂CH₂N(CH₃)₂.

For the purpose of the present disclosure, the term “(cyano)alkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with one or more cyano, e.g., —CN, groups. Non-limitingexemplary (cyano)alkyl groups include —CH₂CH₂CN, —CH₂CH₂CH₂CN, and—CH₂CH₂CH₂CH₂CN.

For the purpose of the present disclosure, the term “carboxamido” asused by itself or as part of another group refers to a radical offormula —C(═O)NR^(20a)R^(20b), wherein R^(20a) and R^(20b) are eachindependently hydrogen, optionally substituted alkyl, optionallysubstituted aryl, or optionally substituted heteroaryl, or R^(20a) andR^(20b) taken together with the nitrogen atom to which they are attachedfrom a 3- to 8-membered heterocyclo group. In one embodiment, R^(20a)and R^(20b) are each independently hydrogen or optionally substitutedalkyl. Non-limiting exemplary carboxamido groups include —CONH₂,—CON(H)CH₃, CON(CH₃)₂, and CON(H)Ph.

For the purpose of the present disclosure, the term “(carboxamido)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with a carboxamido group. Non-limiting exemplary(carboxamido)alkyl groups include —CH₂CONH₂, —C(H)CH₃—CONH₂, and—CH₂CON(H)CH₃.

For the purpose of the present disclosure, the term “sulfonamido” asused by itself or as part of another group refers to a radical of theformula —SO₂NR^(21a)R^(21b), wherein R^(21a) and R^(21b) are eachindependently hydrogen, optionally substituted alkyl, or optionallysubstituted aryl, or R^(21a) and R^(21b) taken together with thenitrogen atom to which they are attached from a 3- to 8-memberedheterocyclo group. Non-limiting exemplary sulfonamido groups include—SO₂NH₂, —SO₂N(H)CH₃, and —SO₂N(H)Ph.

For the purpose of the present disclosure, the term “alkylcarbonyl” asused by itself or as part of another group refers to a carbonyl group,i.e., —C(═O)—, substituted by an alkyl group. A non-limiting exemplaryalkylcarbonyl group is —COCH₃.

For the purpose of the present disclosure, the term “arylcarbonyl” asused by itself or as part of another group refers to a carbonyl group,i.e., —C(═O)—, substituted by an optionally substituted aryl group. Anon-limiting exemplary arylcarbonyl group is —COPh.

For the purpose of the present disclosure, the term “alkylsulfonyl” asused by itself or as part of another group refers to a sulfonyl group,i.e., —SO₂—, substituted by any of the above-mentioned optionallysubstituted alkyl groups. A non-limiting exemplary alkylsulfonyl groupis —SO₂CH₃.

For the purpose of the present disclosure, the term “arylsulfonyl” asused by itself or as part of another group refers to a sulfonyl group,i.e., —SO₂—, substituted by any of the above-mentioned optionallysubstituted aryl groups. A non-limiting exemplary arylsulfonyl group is—SO₂Ph.

For the purpose of the present disclosure, the term “mercaptoalkyl” asused by itself or as part of another group refers to any of theabove-mentioned alkyl groups substituted by a —SH group.

For the purpose of the present disclosure, the term “carboxy” as used byitself or as part of another group refers to a radical of the formula—COOH.

For the purpose of the present disclosure, the term “halo” or “halogen”as used by itself or as part of another group refers to —F, —Cl, Br, or—I.

For the purpose of the present disclosure, the term “nitro” as used byitself or as part of another group refers to a radical of the formula—NO₂.

For the purpose of the present disclosure, the term “cyano” as used byitself or as part of another group refers to a radical of the formula—CN.

For the purpose of the present disclosure, the term “hydroxy” as used byitself or as part of another group refers to a radical of the formula—OH.

For the purpose of the present disclosure, the term “carboxyalkyl” asused by itself or as part of another group refers to any of theabove-mentioned alkyl groups substituted with a —COOH. Non-limitingexemplary carboxyalkyl groups include —CH₂CO₂H and —CH(CH₃)—CO₂H.

For the purpose of the present disclosure, the term “alkoxycarbonyl” asused by itself or as part of another group refers to a carbonyl group,i.e., —C(═O)—, substituted by an alkoxy group. Non-limiting exemplaryalkoxycarbonyl groups are —CO₂Me and —CO₂Et.

For the purpose of the present disclosure, the term“(alkoxycarbonyl)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted with an alkoxycarbonyl group.Non-limiting exemplary (alkoxycarbonyl)alkyl groups include —CH₂CO₂CH₃and —C(H)CH₃—CO₂CH₃.

For the purpose of the present disclosure, the term “aralkyl” as used byitself or as part of another group refers to an alkyl group substitutedwith one, two, or three optionally substituted aryl groups. In oneembodiment, the aralkyl group is a C₁₋₄ alkyl substituted with oneoptionally substituted aryl group. Non-limiting exemplary aralkyl groupsinclude benzyl, phenethyl, —CHPh₂, and —CH(4-F-Ph)₂.

For the purpose of the present disclosure, the term “ureido” as used byitself or as part of another group refers to a radical of the formula—NR^(22a)—C(═O)—NR^(22b)R^(22c), wherein R^(22a) is hydrogen, alkyl, oroptionally substituted aryl, and R^(22b) and R^(22c) are eachindependently hydrogen, alkyl, or optionally substituted aryl, orR^(22b) and R^(22c) taken together with the nitrogen to which they areattached form a 4- to 8-membered heterocyclo group. Non-limitingexemplary ureido groups include —NH—C(C═O)—NH₂ and —NH—C(C═O)—NHCH₃.

For the purpose of the present disclosure, the term “guanidino” as usedby itself or as part of another group refers to a radical of the formula—NR^(23a)—C(═NR²⁴)—NR^(23b)R^(23c) wherein R^(23a), R^(23b), and R^(23c)are each independently hydrogen, alkyl, or optionally substituted aryl,and R²⁴ is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl,carboxamido, or sulfonamido. Non-limiting exemplary guanidino groupsinclude —NH—C(C═NH)—NH₂, —NH—C(C═NCN)—NH₂, —NH—C(C═NH)—NHCH₃.

For the purpose of the present disclosure, the term “azido” as used byitself or as part of another group refers to a radical of the formula—N₃.

For the purpose of the present disclosure, the term “(heterocyclo)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with one, two, or three optionally substituted heterocyclogroups. In one embodiment, the (heterocyclo)alkyl is a C₁₋₄ alkylsubstituted with one optionally substituted heterocyclo group.Non-limiting exemplary (heterocyclo)alkyl groups include:

For the purpose of the present disclosure, the term “(heteroaryl)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with one, two, or three optionally substituted heteroarylgroups. In one embodiment, the (heteroaryl)alkyl group is a C₁₋₄ alkylsubstituted with one optionally substituted heteroaryl group.Non-limiting exemplary (heteroaryl)alkyl groups include:

For the purpose of the present disclosure, the term “alkylcarbonylamino”as used by itself or as part of another group refers to an alkylcarbonylgroup attached to an amino. A non-limiting exemplary alkylcarbonylaminogroup is —NHCOCH₃.

For the purpose of the present disclosure, the term “alkylcarbonyloxy”as used by itself or as part of another group refers to oxygensubstituted by one of the above-mentioned alkylcarbonyl groups. Anon-limiting exemplary alkylcarbonyloxy group is —OCOCH₃.

The present disclosure encompasses any of the Compounds of the Inventionbeing isotopically-labelled (i.e., radiolabeled) by having one or moreatoms replaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively, e.g., ³H, ¹¹C, and¹⁴C. Isotopically-labeled Compounds of the Invention can be prepared bymethods known in the art.

The present disclosure encompasses ³H, ¹¹C, or ¹⁴C radiolabeledCompounds of the Invention and the use of any such compounds asradioligands for their ability to bind to the sodium channel. Forexample, one use of the labeled compounds of the present disclosure isthe characterization of specific receptor binding. Another use of alabeled Compound of the Invention is an alternative to animal testingfor the evaluation of structure-activity relationships. For example, thereceptor assay can be performed at a fixed concentration of a labeledCompound of the Invention and at increasing concentrations of a testcompound in a competition assay. For example, a tritiated Compound ofthe Invention can be prepared by introducing tritium into the particularcompound, for example, by catalytic dehalogenation with tritium. Thismethod may include reacting a suitably halogen-substituted precursor ofthe compound with tritium gas in the presence of a suitable catalyst,for example, Pd/C, in the presence or absence of a base. Other suitablemethods for preparing tritiated compounds can be found in Filer,Isotopes in the Physical and Biomedical Sciences, Vol. 1, LabeledCompounds (Part A), Chapter 6 (1987). ¹⁴C-labeled compounds can beprepared by employing starting materials having a ¹⁴C carbon.

Some of the Compounds of the Invention may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The present disclosure is meant toencompass the use of all such possible forms, as well as their racemicand resolved forms and mixtures thereof. The individual enantiomers canbe separated according to methods known in the art in view of thepresent disclosure. When the compounds described herein contain olefinicdouble bonds or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that they include both. E and Zgeometric isomers. All tautomers are intended to be encompassed by thepresent disclosure as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

The term “treat,” “treating” or “treatment” is meant to encompassadministering to a subject a compound of the present disclosure for thepurposes of amelioration or cure, including preemptive and palliativetreatment.

The term “about,” as used herein in connection with a measured quantity,refers to the normal variations in that measured quantity, as expectedby the skilled artisan making the measurement and exercising a level ofcare commensurate with the objective of measurement and the precision ofthe measuring equipment.

The present disclosure encompasses Compounds of the Invention in saltform, including non-toxic pharmaceutically acceptable salts, andincluding their preparation and use. Examples of pharmaceuticallyacceptable addition salts include inorganic and organic acid additionsalts and basic salts. The pharmaceutically acceptable salts include,but are not limited to, metal salts such as sodium salt, potassium salt,cesium salt and the like; alkaline earth metals such as calcium salt,magnesium salt and the like; organic amine salts such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and thelike; inorganic acid salts such as hydrochloride, hydrobromide,phosphate, sulphate and the like; organic acid salts such as citrate,lactate, tartrate, maleate, fumarate, mandelate, acetate,dichloroacetate, trifluoroacetate, oxalate, formate and the like;sulfonates such as methanesulfonate, benzenesulfonate,p-toluenesulfonate and the like; and amino acid salts such as arginate,asparginate, glutamate and the like.

Acid addition salts can be formed by mixing a solution of the particularCompound of the Invention with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or thelike. Basic salts can be formed by mixing a solution of the compound ofthe present disclosure with a solution of a pharmaceutically acceptablenon-toxic base such as sodium hydroxide, potassium hydroxide, cholinehydroxide, sodium carbonate and the like.

The present disclosure encompasses the preparation and use of solvatesof Compounds of the Invention. Solvates typically do not significantlyalter the physiological activity or toxicity of the compounds, and assuch may function as pharmacological equivalents. The term “solvate” asused herein is a combination, physical association and/or solvation of acompound of the present disclosure with a solvent molecule such as, e.g.a disolvate, monosolvate or hemisolvate, where the ratio of solventmolecule to compound of the present disclosure is about 2:1, about 1:1or about 1:2, respectively. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances, the solvate can be isolated, such as when one or moresolvent molecules are incorporated into the crystal lattice of acrystalline solid. Thus, “solvate” encompasses both solution-phase andisolatable solvates. Compounds of the Invention can be present assolvated forms with a pharmaceutically acceptable solvent, such aswater, methanol, ethanol, and the like, and it is intended that thedisclosure includes both solvated and unsolvated forms of Compounds ofthe Invention. One type of solvate is a hydrate. A “hydrate” relates toa particular subgroup of solvates where the solvent molecule is water.Solvates typically can function as pharmacological equivalents.Preparation of solvates is known in the art. See, for example, M. Cairaet al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes thepreparation of solvates of fluconazole with ethyl acetate and withwater. Similar preparation of solvates, hemisolvates, hydrates, and thelike are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech.,5(1):Article 12 (2004), and A. L. Bingham et al., Chem. Commun. 603-604(2001). A typical, non-limiting, process of preparing a solvate wouldinvolve dissolving a Compound of the Invention in a desired solvent(organic, water, or a mixture thereof) at temperatures above 20° C. toabout 25° C., then cooling the solution at a rate sufficient to formcrystals, and isolating the crystals by known methods, e.g., filtration.Analytical techniques such as infrared spectroscopy can be used toconfirm the presence of the solvent in a crystal of the solvate.

Since Compounds of the Invention are blockers of sodium (Na⁺) channels,a number of diseases and conditions mediated by sodium ion influx can betreated by employing these compounds. The present disclosure is thusdirected generally to a method of treating a disorder responsive to theblockade of sodium channels in a mammal suffering from, or at risk ofsuffering from, said disorder, said method comprising administering tothe mammal an effective amount of one or more Compounds of theInvention.

The present disclosure is further directed to a method of modulatingsodium channels in a mammal in need thereof, said method comprisingadministering to the mammal a modulating-effective amount of at leastone Compound of the Invention.

More specifically, the present disclosure provides a method of treatingstroke, neuronal damage resulting from head trauma, epilepsy, neuronalloss following global and focal ischemia, pain (e.g., acute pain,chronic pain, which includes but is not limited to neuropathic pain,postoperative pain, and inflammatory pain, or surgical pain), aneurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), migraine, manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia in a mammal. In oneembodiment, the disclosure provides a method of treating pain. Inanother embodiment, the type of pain is chronic pain. In anotherembodiment, the type of pain is neuropathic pain. In another embodiment,the type of pain is postoperative pain. In another embodiment, the typeof pain is inflammatory pain. In another embodiment, the type of pain issurgical pain. In another embodiment, the type of pain is acute pain. Inanother embodiment, the treatment of pain (e.g., chronic pain, such asneuropathic pain, postoperative pain, or inflammatory pain, acute painor surgical pain) is preemptive. In another embodiment, the treatment ofpain is palliative. In each instance, such method of treatment requiresadministering to a mammal in need of such treatment an amount of aCompound of the Invention that is therapeutically effective in achievingsaid treatment. In one embodiment, the amount of such compound is theamount that is effective to block sodium channels in vitro. In anotherembodiment, the amount of such compound is the amount that is effectiveto block sodium channels in vivo.

Chronic pain includes, but is not limited to, inflammatory pain,postoperative pain, cancer pain, osteoarthritis pain associated withmetastatic cancer, trigeminal neuralgia, acute herpetic and postherpeticneuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion,occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout,phantom limb pain, burn pain, and other forms of neuralgia, neuropathic,and idiopathic pain syndromes.

Chronic somatic pain generally results from inflammatory responses totissue injury such as nerve entrapment, surgical procedures, cancer orarthritis (Brower, Nature Biotechnology 18:387-391 (2000)).

The inflammatory process is a complex series of biochemical and cellularevents activated in response to tissue injury or the presence of foreignsubstances (Levine, Inflammatory Pain, In: Textbook of Pain, Wall andMelzack eds., 3^(rd) ed., 1994). Inflammation often occurs at the siteof injured tissue, or foreign material, and contributes to the processof tissue repair and healing. The cardinal signs of inflammation includeerythema (redness), heat, edema (swelling), pain and loss of function(ibid.). The majority of patients with inflammatory pain do notexperience pain continually, but rather experience enhanced pain whenthe inflamed site is moved or touched. Inflammatory pain includes, butis not limited to, that associated with osteoarthritis and rheumatoidarthritis.

Chronic neuropathic pain is a heterogeneous disease state with anunclear etiology. In chronic neuropathic pain, the pain can be mediatedby multiple mechanisms. This type of pain generally arises from injuryto the peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. Chronic pain is differentfrom acute pain in that patients suffer the abnormal pain sensationsthat can be described as spontaneous pain, continuous superficialburning and/or deep aching pain. The pain can be evoked by heat-, cold-,and mechano-hyperalgesia or by heat-, cold-, or mechano-allodynia.

Neuropathic pain can be caused by injury or infection of peripheralsensory nerves. It includes, but is not limited to, pain from peripheralnerve trauma, herpes virus infection, diabetes mellitus, causalgia,plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathicpain is also caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Stroke (spinal or brain) and spinal cord injury can alsoinduce neuropathic pain. Cancer-related neuropathic pain results fromtumor growth compression of adjacent nerves, brain, or spinal cord. Inaddition, cancer treatments, including chemotherapy and radiationtherapy, can also cause nerve injury. Neuropathic pain includes but isnot limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

The present disclosure is also directed to the use of a Compound of theInvention in the manufacture of a medicament for treating a disorderresponsive to the blockade of sodium channels (e.g., any of thedisorders listed above) in a mammal suffering from said disorder.

General Synthesis of Compounds

Compounds of the Invention can be prepared using methods known to thoseskilled in the art in view of this disclosure. For example, compoundshaving Formula I can be prepared according to Scheme 1. Briefly,compound A′ or A″ is converted to compound B by treatment with ClSO₃H orCl₂, respectively. Compound B is treated with R¹—NH₂ to form thesulfonamide C. The ester of compound C is reduced to give compound D,and compound D is cyclized to give compound E. Compound E is reactedwith the appropriate reagent (F, G, or H) to give a compound havingFormula I-a, Formula I-b, Formula I-c.

Testing of Compounds

Representative Compounds of the Invention were assessed by sodiummobilization and/or electrophysiological assays for sodium channelblocker activity. One aspect of the present disclosure is based on theuse of the Compounds of the Invention as sodium channel blockers. Basedupon this property, Compounds of the Invention are considered useful intreating a condition or disorder responsive to the blockade of sodiumion channels, e.g., stroke, neuronal damage resulting from head trauma,epilepsy, seizures, general epilepsy with febrile seizures, severemyoclonic epilepsy in infancy, neuronal loss following global and focalischemia, migraine, familial primary erythromelalgia, paroxysmal extremepain disorder, cerebellar atrophy, ataxia, dystonia, tremor, mentalretardation, autism, a neurodegenerative disorder (e.g., Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease),manic depression, tinnitus, myotonia, a movement disorder, cardiacarrhythmia, or providing local anesthesia. Compounds of the Inventionare also expected to be effective in treating pain, e.g., acute pain,chronic pain, which includes but is not limited to, neuropathic pain,postoperative pain, and inflammatory pain, or surgical pain.

More specifically, the present disclosure is directed to Compounds ofthe Invention that are blockers of sodium channels. According to thepresent disclosure, those compounds having useful sodium channelblocking properties exhibit an IC₅₀ for Na_(v)1.1, Na_(v)1.2, Na_(v)1.3,Na_(v)1.4, Na_(v)1.5, Na_(v)1.6, Na_(v)1.7, Na_(v)1.8, and/or Na_(v)1.9of about 100 μM or less, e.g., about 50 μM or less, about 25 μM or less,about 10 μM or less, about 5 μM or less, or about 1 μM or less, insodium mobilization and/or electrophysiological assays. In certainembodiments, Compounds of the Invention exhibit an IC₅₀ for Na_(v)1.7 of100 μM or less, about 50 μM or less, about 25 μM or less, about 10 μM orless, about 5 μM or less, about 1 μM or less, about 0.5 μM or less,about 0.1 μM or less, about 0.05 μM or less, or about 0.01 μM or less.Compounds of the Invention can be tested for their Na⁺ channel blockingactivity using methods known in the art and by the followingfluorescence imaging and electrophysiological in vitro assays and/or invivo assays.

In one embodiment, Compounds of the Invention demonstrate substantiallyno penetration across the CNS blood-brain barrier in a mammal. Suchcompounds are referred to as “peripherally restricted” as a means todesignate their PNS (peripheral nervous system) versus CNS (centralnervous system) tissue selectivity.

In one embodiment, the PNS:CNS concentration ratio of a peripherallyrestricted Compound of the Invention is about 5:1, about 10:1, about20:1, about 30:1; about 50:1; about 100:1, about 250:1, about 500:1,about 1000:1, about 5,000:1, about 10,000:1, or more. Compounds of theInvention can be tested for their ability to penetrate the centralnervous system using in vitro and in vivo methods known in the art.

In Vitro Assay Protocols FLIPR® Assays

Recombinant Na_(v)1.7 Cell Line: In vitro assays were performed in arecombinant cell line expressing cDNA encoding the alpha subunit(Na_(v)1.7, SCN9a, PN1, NE) of human Na_(v)1.7 (Accession No.NM_(—)002977). The cell line was provided by investigators at YaleUniversity (Cummins et al, J. Neurosci. 18(23): 9607-9619 (1998)). Fordominant selection of the Na_(v)1.7-expressing clones, the expressionplasmid co-expressed the neomycin resistance gene. The cell line wasconstructed in the human embryonic kidney cell line, HEK293, under theinfluence of the CMV major late promoter, and stable clones wereselected using limiting dilution cloning and antibiotic selection usingthe neomycin analogue, G418. Recombinant beta and gamma subunits werenot introduced into this cell line. Additional cell lines expressingrecombinant Na_(v)1.7 cloned from other species can also be used, aloneor in combination with various beta subunits, gamma subunits orchaperones.

Non-recombinant Cell Lines Expressing Native Na_(v)1.7: Alternatively,in vitro assays can be performed in a cell line expressing native,non-recombinant Na_(v)1.7, such as the ND7 mouse neuroblastoma X ratdorsal root ganglion (DRG) hybrid cell line ND7/23, available from theEuropean Cell Culture Collection (Cat. No. 92090903, Salisbury,Wiltshire, United Kingdom). The assays can also be performed in othercell lines expressing native, non-recombinant Na_(v)1.7, from variousspecies, or in cultures of fresh or preserved sensory neurons, such asdorsal root ganglion (DRG) cells, isolated from various species. Primaryscreens or counter-screens of other voltage-gated sodium channels canalso be performed, and the cell lines can be constructed using methodsknown in the art, purchased from collaborators or commercialestablishments, and they can express either recombinant or nativechannels. The primary counter-screen is for one of the central neuronalsodium channels, Na_(v)1.2 (rBIIa), expressed in HEK293 host cells(Ilyin et al., Br. J. Pharmacol. 144:801-812 (2005)). Pharmacologicalprofiling for these counter-screens is carried out under conditionssimilar to the primary or alternative Na_(v)1.7 assays described below.

Cell Maintenance:

Unless otherwise noted, cell culture reagents were purchased fromMediatech of Herndon, Va. The recombinant Na_(v)1.7/HEK293 cells wereroutinely cultured in growth medium consisting of Dulbecco's minimumessential medium containing 10% fetal bovine serum (FBS, Hyclone, ThermoFisher Scientific, Logan, Utah), 100 U/mL penicillin, 100 μg/mLstreptomycin, 2-4 mM L-glutamine, and 500 mg/mL G418. For natural,non-recombinant cell lines, the selective antibiotic was omitted, andadditional media formulations can be applied as needed.

Assay Buffer:

The assay buffer was formulated by removing 120 mL from a 1 L bottle offresh, sterile dH₂O (Mediatech, Herndon, Va.) and adding 100 mL of10×HBSS that does not contain Ca⁺⁺ or Mg⁺⁺ (Gibco, Invitrogen, GrandIsland, N.Y.) followed by 20 mL of 1.0 M Hepes, pH 7.3 (FisherScientific, BP299-100). The final buffer consisted of 20 mM Hepes, pH7.3, 1.261 mM CaCl₂, 0.493 mM MgCl₂, 0.407 mM Mg(SO)₄, 5.33 mM KCl,0.441 mM KH₂PO₄, 137 mM NaCl, 0.336 mM Na₂HPO₄ and 0.556 mM D-glucose(Hanks et al., Proc. Soc. Exp. Biol. Med. 71:196 (1949)), and the simpleformulation was typically the basic buffer throughout the assay (i.e.,all wash and addition steps).

CoroNa™ Green AM Na⁺ Dye for Primary Fluorescence Assay:

The fluorescence indicator used in the primary fluorescence assay wasthe cell permeant version of CoroNa™ Green (Invitrogen, MolecularProbes, Eugene, Oreg.), a dye that emits light in the fluorescence range(Harootunian et al., J. Biol. Chem. 264(32):19458-19467 (1989)). Theintensity of this emission, but not the wavelength range, is increasedwhen the dye is exposed to Na⁺ ions, which it can bind with partialselectivity. Cells expressing Na_(v)1.7 or other sodium channels wereloaded with the CoroNa™ Green dye immediately in advance of thefluorescence assay, and then, after agonist stimulation, themobilization of Na⁺ ions was detected as the Na⁺ ions flowed from theextracellular fluid into the cytoplasm through the activated sodiumchannel pores. The dye was stored in the dark as a lyophilized powder,and then an aliquot was dissolved immediately before the cell loadingprocedure, according to the instructions of the manufacturer to a stockconcentration of 10 mM in DMSO. It was then diluted in the assay bufferto a 4× concentrated working solution, so that the final concentrationof dye in the cell loading buffer was 5 μM.

Membrane Potential Dye for Alternative Fluorescence Assays:

A fluorescence indicator that can be used in alternative fluorescenceassays is the blue version membrane potential dye (MDS, MolecularDevices, Sunnyvale, Calif.), a dye that detects changes in moleculesfollowing a change in membrane potential. An increase in fluorescence isexpected if agonist stimulation provokes a change in membrane potential.Cells expressing Na_(v)1.7 or other sodium channels are incubated withthe membrane potential dye 30-60 minutes before the fluorescence assay.In the case of the KCl pre-stimulation version of the assay, the dye andall other components are washed out immediately before the assay, andthe dye is then replaced. In the version lacking KCl pre-stimulation,the dye remains on the cells and is not washed out or replaced. The dyeis stored in the dark as a lyophilized powder, and then an aliquotdissolved in assay buffer to form a 20×-concentrated stock solution thatcan be used for several weeks.

Agonists:

In the fluorescence assays, two agonists were used in combination,namely 1) veratridine; and 2) the venom from the yellow scorpion,Leiurus quinquestriatus hebraeus. Veratridine is an alkaloid smallmolecule that facilitates the capture of channel openings by inhibitinginactivation, and the scorpion venom is a natural preparation thatincludes peptide toxins selective for different subsets of voltage-gatedsodium channels. These scorpion toxins inhibit the fast inactivation oftheir cognate target channels. Stock solutions of the agonists wereprepared to 40 mM in DMSO (veratridine) and 1 mg/mL in dH₂O (scorpionvenom), and then diluted to make a 4× or 2× stock (depending on theparticular assay) in assay buffer, the final concentration being 100 μM(veratridine) and 10 μg/mL (scorpion venom). Both of the agonists werepurchased from Sigma Aldrich, St. Louis, Mo.

Test Compounds:

Test compounds were dissolved in DMSO to yield 10 mM stock solutions.The stock solutions were further diluted using DMSO in 1:3 serialdilution steps with 10 points (10,000 μM, 3.333 μM, 1.111 μM, 370 μM,123 μM, 41 μM, 14 μM, 4.6 μM, 1.5 μM and 0.5 μM). The stock solutionswere further diluted in assay buffer (1:125) as 4× stock serialdilutions with a DMSO concentration of 0.8% (final [DMSO], in the assay,from the compounds component=0.2%), so that the compounds' finalconcentrations in the assay were 20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μMand 0.08 μM, 0.03 μM, 0.01 μM, 0.003 μM and 0.001 μM. If a particulartest article appeared to be especially potent, then the concentrationcurve was adjusted, e.g., to 10-fold lower concentrations, in order toperform the dose-response in a more relevant concentration range.Compound dilutions were added during the dye-loading and pre-stimulationstep, and then again during the fluorescence assay, early in the kineticread. Compound dilutions were added in duplicate rows across the middle80 wells of the 96-well plate, whereas the fully stimulated and thefully inhibited controls (positive and negative) were located in the top4 side wells and the bottom 4 side wells, respectively, on the left andright sides of the assay plate.

Data Analysis:

The data were analyzed according to methods known to those skilled inthe art or using the GraphPad® Prism version 4.0 or higher, Program(available from GraphPad Prism® Software (version 4.0 or higher), SanDiego, Calif.) to determine the IC₅₀ value for the test article. Atleast one standard reference compound was evaluated during eachexperiment.

FLIPR® or FLIPR^(TETRA)® Sodium Dye Assay with KCl and Test ArticlePre-Incubation:

Cells were prepared by plating the recombinant HEK293 cells or otherhost cells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate was then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay. For counter-screens of other voltage-gatedsodium channels, the procedure was very similar, though optimaldensities of cells, media and subsequent assay components can befine-tuned for the particular cell line or isoform.

The next day, at the start of the assay, the media was flicked from thecells and the wells were washed once with 50 μl/well assay buffer (1×Hank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles,CoroNa™ Green AM sodium dye (for cell loading) and KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents were added as follows, immediately after the wash step: 1)first, the compound dilutions and controls were added as 4× concentratesin assay buffer at 50 μL/well; 2) CoroNa™ Green AM dye was diluted fromthe stock solution to 20 μM in assay buffer (4× concentrate) and addedto the plate at 50 μL/well; and 3) finally, a solution of 180 mM KCl(2×) was prepared by diluting a 2M stock solution into assay buffer andthe solution was added to the cells at 100 μl/well. The cells wereincubated at 25° C. in the dark for 30 min. before their fluorescencewas measured.

The plates containing dye-loaded cells were then flicked to remove thepre-incubation components and washed once with 100 μL/well assay buffer.A 100 μL/well aliquot of assay buffer was added back to the plate, andthe real-time assay was commenced. The fluorescence of cells wasmeasured using a fluorescence plate reader (FLIPR^(TETRA)® or FLIPR384®,MDS, Molecular Devices, Sunnyvale, Calif.) Samples were excited byeither a laser or a PMT light source (Excitation wavelength=470-495 nM)and the emissions were filtered (Emission wavelength=515-575 nM). Theadditions of compound and the channel activators in this cell-based,medium-to-high throughput assay were performed on the fluorescence platereader and the results (expressed as relative fluorescence units) werecaptured by means of camera shots every 1-3 sec., then displayed inreal-time and stored. Generally, there was a 15 sec. base line, withcamera shots taken every 1.5 sec., then the test compounds were added,then another 120 sec. baseline was conducted, with camera shots takenevery 3 sec.; and finally, the agonist solution (containing veratridineand scorpion venom) was added. The amplitude of fluorescence increase,resulting from the binding of Na⁺ ions to the CoroNa™ Green dye, wascaptured for ˜180 sec. thereafter. Results were expressed in relativefluorescence units (RFU) and were determined by using the maximum signalduring the latter part of the stimulation; or the maximum minus theminimum during the whole agonist stimulation period; or by taking thearea under the curve for the whole stimulation period.

The assay was performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen were typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

FLIPR® or FLIPR^(TETRA)® Membrane Potential Assay with KCl and TestArticle Pre-Incubation:

Cells are prepared by plating the recombinant HEK293 cells or other hostcells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate is then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay (see, e.g., Benjamin et. al., J. Biomol.Screen 10(4):365-373 (2005)). For screens and counter-screens of othervoltage-gated sodium channels, the assay protocol is similar, thoughoptimal densities of cells, media and subsequent assay components can befine-tuned for the particular cell line or sodium channel isoform beingtested.

The next day, at the start of the assay, the media is flicked from thecells and the wells are washed once with 50 μL/well assay buffer (1×Hank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles, themembrane potential dye (for cell loading), and the KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents are added as follows, immediately after the wash step: 1)first, the compound dilutions and controls are added as 4× concentratesin assay buffer at 50 μL/well; 2) membrane potential dye is diluted fromthe stock solution in assay buffer (4× concentrate) and added to theplate at 50 μL/well; and 3) finally, a solution of 180 mM KCl (2×) isprepared by diluting a 2M stock solution into assay buffer and thesolution added to the cells at 100 μL/well. The cells are incubated at37° C. in the dark for 30-60 min. before their fluorescence is measured.

The plates containing dye-loaded cells are then flicked to remove thepre-incubation components and washed once with 50 μL/well assay buffer.A 50 μL/well aliquot of membrane potential dye is added back to theplate, and the real-time assay is commenced. The fluorescence of cellsis measured using a fluorescence plate reader (FLIPR^(TETRA)® orFLIPR384®, MDS, Molecular Devices, Sunnyvale, Calif.). Samples areexcited by either a laser or a PMT light source (Excitationwavelength=510-545 nM) and the emissions are filtered (Emissionwavelength=565-625 nM). The additions of the compounds (first) and thenthe channel activators (later) in this are performed on the fluorescenceplate reader and the results, expressed as relative fluorescence units(RFU), are captured by means of camera shots every 1-3 sec., thendisplayed in real-time and stored. Generally, there is a 15 sec. baseline, with camera shots taken every 1.5 sec., then the test compoundsare added, then another 120 sec. baseline is conducted, with camerashots taken every 3 sec.; and finally, the agonist solution (containingveratridine and scorpion venom) is added. The amplitude of fluorescenceincrease, resulting from the detection of membrane potential change, iscaptured for ˜120 sec. thereafter. Results are expressed in relativefluorescence units (RFU) and can be determined by using the maximumsignal during the latter part of the stimulation; or the maximum minusthe minimum during the whole stimulation period; or by taking the areaunder the curve for the whole stimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

FLIPR® or FLIPR^(TETRA)® Sodium Dye Assay without KCl and Test ArticlePre-Incubation:

Cells are prepared by plating the recombinant HEK293 cells or other hostcells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate is then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay. For counter-screens of other voltage-gatedsodium channels, the procedure is very similar, though optimal densitiesof cells, media and subsequent assay components can be fine-tuned forthe particular cell line or isoform.

The next day, at the start of the assay, the media is flicked from thecells and the wells washed once with 50 μL/well assay buffer (1× Hank'sbalanced salt solution without sodium bicarbonate or phenol red, 20 mMHepes, pH 7.3). Membrane potential dye is then added to each well of the96-well plate (50 μL/well), from a freshly diluted sample of the stock(now at 4× concentration) in the assay buffer. The cells are incubatedat 37° C. in the dark for 30-60 min. before their fluorescence ismeasured.

In this standard membrane potential assay, the 96-well plate containingdye-loaded cells is then loaded directly onto the plate reader withoutaspirating the dye solution and without any further washing of thecells. The fluorescence of cells is measured using a fluorescence platereader (FLIPR^(TETRA)® or FLIPR384®, MDS, Molecular Devices, Sunnyvale,Calif.). Samples are excited by either a laser or a PMT light source(Excitation wavelength=510-545 nM) and the emissions are filtered(Emission wavelength=565-625 nM). The additions of the compounds (first,50 μL/well from a 4× stock plate) and then the channel activators(later, 100 μL/well from a 2× stock solution) in this kinetic assay areperformed on the fluorescence plate reader and the results, expressed asrelative fluorescence units (RFU), are captured by means of camera shotsevery 1-3 sec., then displayed in real-time and stored. Generally, thereis a 15 sec. base line, with camera shots taken every 1.5 sec., then thetest compounds are added, then another 120 sec. baseline is conducted,with camera shots taken every 3 sec.; and finally, the agonist solution(containing veratridine and scorpion venom) is added. The amplitude offluorescence increase, resulting from the detection of membranepotential change, is captured for ˜120 sec. thereafter. Results areexpressed in relative fluorescence units (RFU) and can be determined byusing the maximum signal during the latter part of the stimulation; orthe maximum minus the minimum during the whole stimulation period; or bytaking the area under the curve for the whole stimulation period.

The assay can be performed as a screening assay as well, with the testarticles present in standard amounts (e.g. 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

Electrophysiology Assay

Cells:

The hNa_(v)1.7 expressing HEK-293 cells are plated on 35 mm culturedishes pre-coated with poly-D-lysine in standard DMEM culture media(Mediatech, Inc., Herndon, Va.) and incubated in a 5% CO₂ incubator at37° C. Cultured cells are used approximately 12-48 hours after plating.

Electrophysiology:

On the day of experimentation, the 35 mm dish is placed on the stage ofan inverted microscope equipped with a perfusion system thatcontinuously perfuses the culture dish with fresh recording media. Agravity driven superfusion system is used to apply test solutionsdirectly to the cell under evaluation. This system consists of an arrayof glass pipettes connected to a motorized horizontal translator. Theoutlet of the shooter is positioned approximately 100 μm from the cellof interest.

Whole cell currents are recorded using the whole-cell patch clampconfiguration using an Axopatch 200B amplifier (Axon Instruments, FosterCity Calif.), 1322A A/D converter (Axon Instruments) and pClamp software(v. 8; Axon Instruments) and stored on a personal computer. Gigasealsare formed and the whole-cell configuration is established in voltageclamp mode, and membrane currents generated by hNa_(v)1.7 are recordedin gap-free mode. Borosilicate glass pipettes have resistance valuesbetween 1.5 and 2.0 MΩ when filled with pipette solution and seriesresistance (<5 MΩ) is compensated 75-80%. Signals are sampled at 50 kHzand low pass filtered at 3 kHz.

Voltage Protocols:

After establishing the whole-cell configuration in voltage clamp mode,voltage protocols are run to establish the 1) test potential, 2) holdingpotential, and 3) the conditioning potential for each cell.

After establishing the whole-cell configuration in voltage clamp mode, astandard I-V protocol is run to determine the potential at which themaximal current (I_(max)) is elicited. This potential is the testpotential (V_(t)). To determine a conditioning potential at which 100%of channels are in the inactivated state, a standard steady-stateinactivation (SSIN) protocol is run using a series of fifteen 100ms-long depolarizing prepulses, incrementing in 10 mV steps, immediatelyfollowed by a 5 ms testing pulse, V_(t), to V_(max). This protocol alsopermits determination of the holding potential at which all channels arein the resting state.

For compounds causing significant retardation of recovery frominactivation, an estimate of the affinity for the inactivated state ofthe channel (K_(i)) is generated using the following protocol. From thenegative, no residual inactivation, holding potential, the cell isdepolarized to the conditioning voltage for 2-5 seconds, returned to thenegative holding potential for 10-20 ms to relieve fast inactivation andthen depolarized to the test potential for ˜15 ms. This voltage protocolis repeated every 10-15 seconds, first to establish a baseline in theabsence of the test compound, then in the presence of the test compound.

After a stable baseline is established, the test compound is applied andblock of the current elicited by the test pulse assessed. In some cases,multiple cumulative concentrations are applied to identify aconcentration that blocked between 40-60% of this current. Washout ofthe compound is attempted by superfusing with control solution oncesteady-state block is observed. An estimate of the K_(i) is calculatedas follows:

K _(i)=[drug]*{FR/(1−FR)},  Eq. 1

where [drug] is the concentration of a drug, and

FR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude. If multiple concentrations areused, K_(i) is determined from the fit of a logistic equation to FRsplotted against corresponding drug concentrations.

In the alternative, the voltage clamp protocol to examine hNa_(v)1.7currents is as follows. First, the standard current-voltage relationshipis tested by pulsing the cell from the holding voltage (V_(h)) of −120mV by a series of 5 msec long square-shaped test pulses incrementing in+10 mV steps over the membrane voltage range of −90 mV to +60 mV at thepace of stimulation of 0.5 Hz. This procedure determines the voltagethat elicits the maximal current (V_(max)). Second, V_(h) is re-set to−120 mV and a steady-state inactivation (SSIN) curve is taken by thestandard double-pulse protocol: 100 ms depolarizing pre-pulse isincremented in steps of +10 mV (voltage range from −90 mV to 0 mV)immediately followed by the 5 ms long test pulse to −10 mV at the paceof stimulation of 0.2 Hz. This procedure determines the voltage of fullinactivation (V_(full)). Third, the cell is repeatedly stimulated withthe following protocol, first in the absence of the test compound thenin its presence. The protocol consists of depolarizing the cell from theholding potential of −120 mV to the V_(full) value for 4.5 seconds thenrepolarizing the cell to the holding potential for 10 ms before applyingthe test pulse to the V_(max) for 5 ms. The amount of inhibitionproduced by the test compound is determined by comparing the currentamplitude elicited by the test pulse in the absence and presence of thecompound.

In a further alternative, the voltage clamp protocol to examinehNa_(v)1.7 currents is as follows. After establishing the whole-cellconfiguration in voltage clamp mode, two voltage protocols are run toestablish: 1) the holding potential; and 2) the test potential for eachcell.

Resting Block:

To determine a membrane potential at which the majority of channels arein the resting state, a standard steady-state inactivation (SSIN)protocol is run using 100 ms prepulses×10 mV depolarizing steps. Theholding potential for testing resting block (Vh₁) is 20 mV morehyperpolarized than the first potential where inactivation is observedwith the inactivation protocol.

From this holding potential a standard I-V protocol is run to determinethe potential at which the maximal current (Imax) is elicited. Thispotential is the test potential (Vt).

The compound testing protocol is a series of 10 ms depolarizations fromthe Vhi (determined from the SSIN) to the Vt (determined from the I-Vprotocol) repeated every 10-15 seconds. After a stable baseline isestablished, a high concentration of a test compound (highestconcentration solubility permits or that which provides ˜50% block) isapplied and block of the current assessed. Washout of the compound isattempted by superfusing with control solution once steady-state blockis observed. The fractional response is calculated as follows:

K _(r)=[drug]*{FR/(1−FR)},  Eq. 3

where [drug] is the concentration of a drug, and

FR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude and is used for estimating restingblock dissociation constant, K_(r).

Block of Inactivated Channels:

To assess the block of inactivated channels the holding potential isdepolarized such that 20-50% of the current amplitude is reduced whenpulsed to the same Vt as above. The magnitude of this depolarizationdepends upon the initial current amplitude and the rate of current lossdue to slow inactivation. This is the second holding potential (Vh₂).The current reduction is recorded to determine the fraction of availablechannels at this potential (h).

h=I @Vh2/Imax.  Eq. 4

At this membrane voltage a proportion of channels is in the inactivatedstate, and thus inhibition by a blocker includes interaction with bothresting and inactivated channels.

To determine the potency of the test compound on inactivated channels, aseries of currents are elicited by 10 ms voltage steps from Vh2 to Vtevery 10-15 seconds. After establishing a stable baseline, the lowconcentration of the compound is applied. In some cases, multiplecumulative concentrations will have to be applied to identify aconcentration that blocks between 40-60% of the current. Washout isattempted to re-establish baseline. Fractional responses are measuredwith respect to a projected baseline to determine K_(app).

K _(app)=[drug]*{FR/(1−FR)},  Eq. 5

where [drug] is the concentration of a drug.

This K_(app) value, along with the calculated K_(r) and h values, areused to calculate the affinity of the compound for the inactivatedchannels (K_(i)) using the following equation:

K _(i)=(1−h)/((1/K _(app))−(h/K _(r))).  Eq. 6

Solutions and Chemicals:

For electrophysiological recordings the external solution is eitherstandard, DMEM supplemented with 10 mM HEPES (pH adjusted to 7.34 withNaOH and the osmolarity adjusted to 320) or Tyrodes salt solution(Sigma, USA) supplemented with 10 mM HEPES (pH adjusted to 7.4 withNaOH; osmolarity=320). The internal pipette solution contained (in mM):NaCl (10), CsF (140), CaCl₂ (1), MgCl₂ (5), EGTA (11), HEPES (10: pH7.4, 305 mOsm). Compounds are prepared first as series of stocksolutions in DMSO and then dissolved in external solution; DMSO contentin final dilutions do not exceed 0.3%. At this concentration, DMSO doesnot affect sodium currents. Vehicle solution used to establish base linecontains 0.3% DMSO.

Data Analysis:

Data is analyzed off-line using Clampfit software (pClamp, v. 8; AxonInstruments) and graphed using GraphPad Prism® (v: 4.0 or higher)software.

In Vivo Assay for Pain

Compounds of the Invention can be tested for their antinociceptiveactivity in the formalin model as described in Hunskaar et al., J.Neurosci. Methods 14: 69-76 (1985). Male Swiss Webster NIH mice (20-30g; Harlan, San Diego, Calif.) can be used in all experiments. Food iswithdrawn on the day of experiment. Mice are placed in Plexiglass jarsfor at least 1 hour to acclimate to the environment. Following theacclimation period, mice are weighed and given either the compound ofinterest administered i.p. or p.o., or the appropriate volume of vehicle(for example, 10% Tween-80 or 0.9% saline, and other pharmaceuticallyacceptable vehicles) as control. Fifteen minutes after the i.p. dosing,and 30 minutes after the p.o. dosing mice are injected with formalin (20μL of 5% formaldehyde solution in saline) into the dorsal surface of theright hind paw. Mice are transferred to the Plexiglass jars andmonitored for the amount of time spent licking or biting the injectedpaw. Periods of licking and biting are recorded in 5-minute intervalsfor 1 hour after the formalin injection. All experiments are done in ablinded manner during the light cycle. The early phase of the formalinresponse is measured as licking/biting between 0-5 minutes, and the latephase is measured from 15-50 minutes. Differences between vehicle anddrug treated groups can be analyzed by one-way analysis of variance(ANOVA). A P value <0.05 is considered significant. Compounds areconsidered to be efficacious for treating acute and chronic pain if theyhave activity in blocking both the early and second phase offormalin-induced paw-licking activity.

In Vivo Assays for Inflammatory or Neuropathic Pain

Test Animals:

Each experiment uses rats weighing between 200-260 g at the start of theexperiment. The rats are group-housed and have free access to food andwater at all times, except prior to oral administration of a testcompound when food is removed for 16 h before dosing. A control groupacts as a comparison to rats treated with a Compound of the Invention.The control group is administered the carrier as used for the testcompound. The volume of carrier administered to the control group is thesame as the volume of carrier and test compound administered to the testgroup.

Inflammatory Pain:

To assess the actions of Compounds of the Invention on the treatment ofinflammatory pain the Freund's complete adjuvant (“FCA”) model ofinflammatory pain is used. FCA-induced inflammation of the rat hind pawis associated with the development of persistent inflammatory mechanicaland thermal hyperalgesia and provides reliable prediction of theanti-hyperalgesic action of clinically useful analgesic drugs (Bartho etal., Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)).The left hind paw of each animal is administered a 50 μL intraplantarinjection of 50% FCA. 24 hour post injection, the animal is assessed forresponse to noxious mechanical stimuli by determining the paw withdrawalthreshold (PWT), or to noxious thermal stimuli by determining the pawwithdrawal latency (PWL), as described below. Rats are then administereda single injection of either a test compound or 30 mg/Kg of a positivecontrol compound (such as indomethacin, Celebrex, or naproxen sodium),or an equal volume of vehicle as a negative control. Responses tonoxious mechanical or thermal stimuli are then determined 1, 3, 5 and 24hours post administration (admin). Percentage reversal of hyperalgesiafor each animal is defined as:

${\% \mspace{14mu} {reversal}} = {\frac{\begin{bmatrix}{\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right)\end{bmatrix}}{\begin{bmatrix}{\left( {{baseline}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right)\end{bmatrix}} \times 100}$

Neuropathic Pain:

To assess the actions of the test compounds for the treatment ofneuropathic pain the Seltzer model or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats(Seltzer et al., Pain 43:205-218 (1990)). Partial ligation of the leftsciatic nerve is performed under isoflurane/O₂ inhalation anesthesia.Following induction of anesthesia, the left thigh of the rat is shavedand the sciatic nerve exposed at high thigh level through a smallincision and is carefully cleared of surrounding connective tissues at asite near the trocanther just distal to the point at which the posteriorbiceps semitendinosus nerve branches off of the common sciatic nerve. A7-0 silk suture is inserted into the nerve with a ⅜ curved,reversed-cutting mini-needle and tightly ligated so that the dorsal ⅓ to½ of the nerve thickness is held within the ligature. The wound isclosed with a single muscle suture (4-0 nylon (Vicryl)) and vetbondtissue glue. Following surgery, the wound area is dusted with antibioticpowder. Sham-treated rats undergo an identical surgical procedure exceptthat the sciatic nerve is not manipulated. Following surgery, animalsare weighed and placed on a warm pad until they recover from anesthesia.Animals are then returned to their home cages until behavioral testingbegins. The animals are assessed for response to noxious mechanicalstimuli by determining PWT, as described below, prior to surgery(baseline), then immediately prior to and 1, 3, and 5 hours after drugadministration for the ipsilateral (same side as the injury) rear paw ofthe animal. Percentage reversal of neuropathic hyperalgesia is definedas:

${\% \mspace{14mu} {reversal}} = {\frac{\begin{bmatrix}{{\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}} \right) -}\mspace{11mu}} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)\end{bmatrix}}{\begin{bmatrix}{\left( {{baseline}\mspace{14mu} {PWT}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)\end{bmatrix}} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anesthesia. Following induction of anesthesia a 3 cm incisionis made and the left paraspinal muscles are separated from the spinousprocess at the L₄-S₂ levels. The L₆ transverse process is carefullyremoved with a pair of small rongeurs to identify visually the L₄-L₆spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) is (are)isolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is (are)not manipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a Compound of theInvention for the left rear paw of the animal. The animals can also beassessed for response to noxious thermal stimuli or for tactileallodynia, as described below. The Chung model for neuropathic pain isdescribed in Kim et al., Pain 50(3):355-363 (1992).

Tactile Allodynia:

Sensitivity to non-noxious mechanical stimuli can be measured in animalsto assess tactile allodynia. Rats are transferred to an elevated testingcage with a wire mesh floor and allowed to acclimate for five to tenminutes. A series of von Frey monofilaments are applied to the plantarsurface of the hindpaw to determine the animal's withdrawal threshold.The first filament used possesses a buckling weight of 9.1 gms (0.96 logvalue) and is applied up to five times to see if it elicits a withdrawalresponse. If the animal has a withdrawal response, then the nextlightest filament in the series would be applied up to five times todetermine if it also could elicit a response. This procedure is repeatedwith subsequent lesser filaments until there is no response and theidentity of the lightest filament that elicits a response is recorded.If the animal does not have a withdrawal response from the initial 9.1gms filament, then subsequent filaments of increased weight are applieduntil a filament elicits a response and the identity of this filament isrecorded. For each animal, three measurements are made at every timepoint to produce an average withdrawal threshold determination. Testscan be performed prior to, and at 1, 2, 4 and 24 hours post drugadministration.

Mechanical Hyperalgesia:

Sensitivity to noxious mechanical stimuli can be measured in animalsusing the paw pressure test to assess mechanical hyperalgesia. In rats,hind paw withdrawal thresholds (“PWT”), measured in grams, in responseto a noxious mechanical stimulus are determined using an analgesymeter(Model 7200, commercially available from Ugo Basile of Italy), asdescribed in Stein (Biochemistry & Behavior 31: 451-455 (1988)). Therat's paw is placed on a small platform, and weight is applied in agraded manner up to a maximum of 250 grams. The endpoint is taken as theweight at which the paw is completely withdrawn. PWT is determined oncefor each rat at each time point. PWT can be measured only in the injuredpaw, or in both the injured and non-injured paw. In one non-limitingembodiment, mechanical hyperalgesia associated with nerve injury inducedpain (neuropathic pain) can be assessed in rats. Rats are tested priorto surgery to determine a baseline, or normal, PWT. Rats are testedagain 2 to 3 weeks post-surgery, prior to, and at different times after(e.g. 1, 3, 5 and 24 hr) drug administration. An increase in PWTfollowing drug administration indicates that the test compound reducesmechanical hyperalgesia associated with nerve injury. In anothernon-limiting embodiment, mechanical hyperalgesiaq associated withinflammatory pain can be assessed in rats. Rats are tested prior toinduction of inflammation (such as by intraplantar injection of FCA) todetermine a baseline, or normal PWT. Rats are tested again 24 hoursafter FCA injection, prior to, and at diferent times after (e.g. 1, 3,5, and 24 hr) drug administration. An increase in PWT following drugadministration imndicates that the test compound reduces mechanicalhyperalgesia associated with inflammation.

In Vivo Assay for Anticonvulsant Activity

Compounds of the Invention can be tested for in vivo anticonvulsantactivity after i.v., p.o., or i.p. injection using any of a number ofanticonvulsant tests in mice or rats, including the maximum electroshockseizure test (MES). Maximum electroshock seizures are induced in maleNSA mice weighing between 15-20 g and in male Sprague-Dawley ratsweighing between 200-225 g by application of current (for mice: 50 mA,60 pulses/sec, 0.8 msec pulse width, 1 sec duration, D.C.; for rats: 99mA, 125 pulses/sec, 0.8 msec pulse width, 2 sec duration, D.C.) using aUgo Basile ECT device (Model 7801). Mice are restrained by gripping theloose skin on their dorsal surface and saline-coated corneal electrodesare held lightly against the two corneae. Rats are allowed free movementon the bench top and ear-clip electrodes are used. Current is appliedand animals are observed for a period of up to 30 seconds for theoccurrence of a tonic hindlimb extensor response. A tonic seizure isdefined as a hindlimb extension in excess of 90 degrees from the planeof the body. Results can be treated in a quantal manner.

Pharmaceutical Compositions

Compounds of the Invention can be administered to a mammal in the formof a raw chemical without any other components present. More preferably,however, Compounds of the Invention are administered to a mammal as partof a pharmaceutical composition containing the compound combined with asuitable pharmaceutically acceptable carrier. Such a carrier can beselected from pharmaceutically acceptable excipients and auxiliaries.

Pharmaceutical compositions within the scope of the present disclosureinclude all compositions where a Compound of the Invention is combinedwith one or more pharmaceutically acceptable carriers. In oneembodiment, the Compound of the Invention is present in the compositionin an amount that is effective to achieve its intended therapeuticpurpose when administered to a mammal in need of such treatment. Whileindividual needs may vary, a determination of optimal ranges ofeffective amounts of each compound is within the skill of the art.Typically, a Compound of the Invention can be administered to a mammal,e.g., a human, orally at a dose of from about 0.0025 to about 1500 mgper kg body weight of the mammal, or an equivalent amount of apharmaceutically acceptable salt, or solvate thereof, per day to treatthe particular disorder. A useful oral dose of a Compound of theInvention administered to a mammal is from about 0.0025 to about 50 mgper kg body weight of the mammal, or an equivalent amount of thepharmaceutically acceptable salt, or solvate thereof. For intramuscularinjection, the dose is typically about one-half of the oral dose.

A unit oral dose may comprise from about 0.01 mg to about 1 g of theCompound of the Invention, e.g., about 0.01 mg to about 500 mg, about0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, 0.01 mg to about50 mg, e.g., about 0.1 mg to about 10 mg, of the compound. The unit dosecan be administered one or more times daily, e.g., as one or moretablets or capsules, each containing from about 0.01 mg to about 1 g ofthe compound, or an equivalent amount of a pharmaceutically acceptablesalt or solvate thereof.

A pharmaceutical composition of the present disclosure can beadministered to any animal that may experience the beneficial effects ofa Compound of the Invention. Foremost among such animals are mammals,e.g., humans and companion animals, although the disclosure is notintended to be so limited.

A pharmaceutical composition of the present disclosure can beadministered by any means that achieves its intended purpose. Forexample, administration can be by the oral, parenteral, subcutaneous,intravenous, intramuscular, intraperitoneal, transdermal, intranasal,transmucosal, rectal, intravaginal or buccal route, or by inhalation.The dosage administered and route of administration will vary, dependingupon the circumstances of the particular subject, and taking intoaccount such factors as age, gender, health, and weight of therecipient, condition or disorder to be treated, kind of concurrenttreatment, if any, frequency of treatment, and the nature of the effectdesired.

Pharmaceutical compositions of the invention can take the form ofsolutions, suspensions, emulsions, tablets, pills, pellets,multi-particulates, capsules, capsules containing liquids, capsulescontaining powders, capsules containing multi-particulates, lozenges,sustained-release formulations, thin films, suppositories, aerosols,sprays, or any other form suitable for use. In one embodiment, thecomposition is in the form of a capsule (see, e.g., U.S. Pat. No.5,698,155). Other examples of suitable pharmaceutical excipients aredescribed in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R.Gennaro ed., 19th ed. 1995), incorporated herein by reference. In oneembodiment, a pharmaceutical composition of the present disclosure canbe administered orally and is formulated into tablets, dragees, capsulesor an oral liquid preparation. In one embodiment, the oral formulationcomprises extruded multiparticulates comprising the Compound of theInvention.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered rectally, and is formulated in suppositories.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered by injection.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered transdermally.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered by inhalation or by intranasal or transmucosaladministration.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered by the intravaginal route.

A pharmaceutical composition of the present disclosure can contain fromabout 0.01 to 99 percent by weight, and preferably from about 0.25 to 75percent by weight, of active compound(s).

A method of the present disclosure, such as a method of treating adisorder responsive to the blockade of sodium channels in a mammal inneed thereof, can further comprise administering a second therapeuticagent to the mammal in combination with a Compound of the Invention. Inone embodiment, the other therapeutic agent is administered in aneffective amount.

Effective amounts of the other therapeutic agents are known to thoseskilled in the art. However, it is well within the skilled artisan'spurview to determine the other therapeutic agent's optimaleffective-amount range.

Compounds of the Invention (i.e., the first therapeutic agent) and thesecond therapeutic agent can act additively or, in one embodiment,synergistically. Alternatively, the second therapeutic agent can be usedto treat a disorder or condition that is different from the disorder orcondition for which the first therapeutic agent is being administered,and which disorder or condition may or may not be a condition ordisorder as defined herein. In one embodiment, a Compound of theInvention is administered concurrently with a second therapeutic agent;for example, a single composition comprising both an effective amount ofa Compound of the Invention and an effective amount of the secondtherapeutic agent can be administered. Accordingly, the presentdisclosure further provides a pharmaceutical composition comprising acombination of a Compound of the Invention, the second therapeuticagent, and a pharmaceutically acceptable carrier. Alternatively, a firstpharmaceutical composition comprising an effective amount of a Compoundof the Invention and a second pharmaceutical composition comprising aneffective amount of the second therapeutic agent can be concurrentlyadministered. In another embodiment, an effective amount of a Compoundof the Invention is administered prior or subsequent to administrationof an effective amount of the second therapeutic agent. In thisembodiment, the Compound of the Invention is administered while thesecond therapeutic agent exerts its therapeutic effect, or the secondtherapeutic agent is administered while the Compound of the Inventionexerts its therapeutic effect for treating a disorder or condition.

The second therapeutic agent can be an opioid agonist, a non-opioidanalgesic, a non-steroidal anti-inflammatory agent, an antimigraineagent, a Cox-II inhibitor, a β-adrenergic blocker, an anticonvulsant, anantidepressant, an anticancer agent, an agent for treating addictivedisorder, an agent for treating Parkinson's disease and parkinsonism, anagent for treating anxiety, an agent for treating epilepsy, an agent fortreating a seizure, an agent for treating a stroke, an agent fortreating a pruritic condition, an agent for treating psychosis, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, or an agent for treating depression, or a mixturethereof. For a more detailed description of the NSAIDs, see Paul A.Insel, Analgesic Antipyretic and Antiinflammatory Agents and DrugsEmployed in the Treatment of Gout, in Goodman & Gilman's ThePharmacological Basis of Therapeutics 617-57 (Perry B. Molinhoff andRaymond W. Ruddon eds., 9th ed 1996) and Glen R. Hanson, Analgesic,Antipyretic and Anti Inflammatory Drugs in Remington: The Science andPractice of Pharmacy Vol. II 1196-1221 (A. R. Gennaro ed. 19th ed. 1995)which are hereby incorporated by reference in their entireties.

A pharmaceutical composition of the present disclosure is manufacturedin a manner which itself will be known in view of the instantdisclosure, for example, by means of conventional mixing, granulating,dragee-making, dissolving, extrusion, or lyophilizing processes. Thus,pharmaceutical compositions for oral use can be obtained by combiningthe active compound with solid excipients, optionally grinding theresulting mixture and processing the mixture of granules, after addingsuitable auxiliaries, if desired or necessary, to obtain tablets ordragee cores.

Suitable excipients include fillers such as saccharides (for example,lactose, sucrose, mannitol or sorbitol), cellulose preparations, calciumphosphates (for example, tricalcium phosphate or calcium hydrogenphosphate), as well as binders such as starch paste (using, for example,maize starch, wheat starch, rice starch, or potato starch), gelatin,tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one ormore disintegrating agents can be added, such as the above-mentionedstarches and also carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodiumalginate.

Auxiliaries are typically flow-regulating agents and lubricants such as,for example, silica, talc, stearic acid or salts thereof (e.g.,magnesium stearate or calcium stearate), and polyethylene glycol. Drageecores are provided with suitable coatings that are resistant to gastricjuices. For this purpose, concentrated saccharide solutions can be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate can be used. Dye stuffs orpigments can be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Examples of other pharmaceutical preparations that can be used orallyinclude push-fit capsules made of gelatin, or soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain a compound in the form of granules, which can bemixed with fillers such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers, or in the form of extruded multiparticulates. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as fatty oils or liquid paraffin. In addition,stabilizers can be added.

Possible pharmaceutical preparations for rectal administration include,for example, suppositories, which consist of a combination of one ormore active compounds with a suppository base. Suitable suppositorybases include natural and synthetic triglycerides, and paraffinhydrocarbons, among others. It is also possible to use gelatin rectalcapsules consisting of a combination of active compound with a basematerial such as, for example, a liquid triglyceride, polyethyleneglycol, or paraffin hydrocarbon.

Suitable formulations for parenteral administration include aqueoussolutions of the active compound in a water-soluble form such as, forexample, a water-soluble salt, alkaline solution, or acidic solution.Alternatively, a suspension of the active compound can be prepared as anoily suspension. Suitable lipophilic solvents or vehicles for such assuspension may include fatty oils (for example, sesame oil), syntheticfatty acid esters (for example, ethyl oleate), triglycerides, or apolyethylene glycol such as polyethylene glycol-400 (PEG-400). Anaqueous suspension may contain one or more substances to increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran. The suspension mayoptionally contain stabilizers.

The following examples are illustrative, but not limiting, of thecompounds, compositions, and methods of the present disclosure. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the disclosure.

EXAMPLES Example 1 Synthesis of Compound 12

To a mixture of compound 8 (3.334 g, 16.65 mmol, 1 eq) in acetonitrile(40 mL) was added KNO₃ (4.210 g, 41.64 mmol, 2.5 eq). The mixture wascooled on an ice bath, then a solution of sulfuryl chloride (3.40 mL,41.94 mmol, 2.5 eq.) in acetonitrile (10 mL) was added dropwise over ˜4minutes. After 10 minutes, the ice bath was removed and the reaction wasstirred at ambient temperature overnight. The reaction mixture waspartitioned between 250 mL Et₂O and 50 mL saturated NaHCO₃, and theorganics were isolated and washed successively with 50 mL saturatedNaHCO₃ and 50 mL brine. The organics were dried with MgSO₄, filtered andevaporated in vacuo to give compound 9 as a yellow crystalline solid(4.528 g, quant.). LC/MS, m/z=267 [M+H]⁺ (Calc: 266).

To a mixture of compound 9 (3.151 g, 11.82 mmol, 1 eq) and2-aminothiazole (2.370 g, 23.67 mmol, 2 eq.) was added 1:1 pyridine/DCM(40 mL). After one hour of stirring at ambient temperature, the mixturewas heated at reflux overnight. The reaction mixture was evaporated invacuo, diluted with acetone, evaporated in vacuo again, diluted oncemore with MeOH, and evaporated in vacuo. The residue was chromatographedover silica gel with 25-75% acetone in hexanes. The product fractionswere evaporated in vacuo to give compound 10 as a pink-range powder(1.750 g, 5.30 mmol, 45% yield). LC/MS, m/z=331 [M+H]⁺ (Calc: 330).

To a mixture of compound 10 (1.750 g, 5.30 mmol, 1 eq) in THF (50 mL)was added NaBH₄ (1.223 g, 32.33 mmol) and MeOH (10 mL). The mixture washeated at reflux for 1.5 hours then additional NaBH₄ (1.015 g, 26.83mmol) was added. After two more hours, additional NaBH₄ (1.008 g, 26.65mmol) was added. Lastly, after one hour, additional NaBH₄ (1.008 g,26.65 mmol) was added, and the reaction was stirred at reflux overnight.After cooling, the solids were filtered off and rinsed with Et₂O. MeOHwas added to the filtrate the diluted filtrate was evaporated in vacuo.The residue was partitioned between 200 mL EtOAc and 25 mL saturatedNH₄Cl, and the organics were isolated and washed successively with 25 mLwater then 25 mL brine. The organics were dried with MgSO₄, filtered andevaporated in vacuo. The residue was taken up in a smaller amount ofEtOAc and filtered again to remove turbidity. The filtrate wasevaporated in vacuo to give compound 11 (1.433 g, 4.97 mmol, 94%).LC/MS, m/z=289 [M+H]⁺ (Calc: 288).

To a mixture of triphenyl phosphine (1.564 g, 5.96 mmol, 1.2 eq) in THF(20 mL) was added DEAD (2.70 mL, 40% solution in toluene, 5.94 mmol, 1.2eq). The reaction was stirred for 2 minutes then added to a solution ofcompound 11 (1.433 g, 4.97 mmol, 1 eq) in THF (40 mL). After 30 minutes,the reaction was diluted with MeOH, evaporated in vacuo, andchromatographed over silica gel with 25-75% acetone in hexanes. Theproduct fractions were evaporated in vacuo and the residue trituratedwith 5 mL acetone. The solid product was collected via filtration andrinsed once with 1 mL acetone. A second crop of product was obtained byevaporation of the filtrate in vacuo, triturating the residue with 4 mLMeOH, filtering off the resulting solid, and rinsing with 1 mL MeOH.Both crops of solid were combined and dried under vacuum at 40° C. togive compound 12 as a pale tan powder (0.614 g, 2.27 mmol, 46% yield).¹H NMR δ_(H) (400 MHz, DMSO-d₆) 7.87 (dd, J=8.8, 5.5 Hz, 1H), 7.55 (dd,J=9.0, 2.6 Hz, 1H), 7.48 (dt, J=8.8, 2.6 Hz, 1H), 7.28 (d, J=4.8 Hz,1H), 6.97 (d, J=4.8 Hz, 1H), 5.66 (s, 2H); LC/MS, m/z=271 [M+H]⁺ (Calc:270).

Example 2 Synthesis of Compound 17

Compound 13 (10.003 g, 59.49 mmol, 1 eq.) was cooled on an ice-saltbath. To this was added chlorosulfonic acid (45 mL, 677 mmol, 11 eq.)dropwise over ˜45 minutes. The ice bath was allowed to melt and thereaction warmed up and stirred overnight. The reaction mixture was thencarefully poured onto ˜500 g ice chips then extracted three times with200 mL DCM. The combined organics were washed once with 50 mL saturatedNaHCO₃ then once with 50 mL brine. The organics were dried with MgSO₄,filtered and evaporated in vacuo to give compound 14 as a tancrystalline solid (8.06 g, 30.22 mmol, 51% yield). LC/MS, m/z=267 [M+H]⁺(Calc: 266).

To a mixture of compound 14 (8.06 g, 30.22 mmol, 1 eq) and2-aminothiazole (6.060 g, 60.52 mmol, 2 eq) was added 1:1 pyridine/DCM(100 mL). The mixture was heated at reflux for 2 days then quenched withMeOH and evaporated in vacuo. The residue was partitioned between 200 mLEtOAc and 50 mL 1N HCl which caused a solid to form. The solid wascollected via filtration and washed once with 10 mL MeOH. The materialwas dried under vacuum at ˜40-50° C. to give compound 15 as apeach-colored powder (4.73 g, 14.3 mmol, 47% yield). LC/MS, m/z=331[M+H]⁺ (Calc: 330).

To a mixture of compound 15 (4.73 g, 14.3 mmol, 1 eq) in THF (100 mL)was added NaBH₄ (3.259 g, 86.15 mmol, 6 eq) and MeOH (10 mL). Themixture was heated at reflux for 3 days. MeOH was added to the reactionmixture then it was evaporated in vacuo. The residue was partitionedbetween 250 mL EtOAc and 100 mL 10% citric acid solution. The organicswere isolated and washed once with 50 mL brine. The organics were driedwith Na₂SO₄, filtered and evaporated in vacuo to give compound 16 whichwas carried on as-is.

To a mixture of triphenyl phosphine (4.517 g, 17.22 mmol, 1.2 eq) in THF(25 mL) was added DEAD (7.9 mL, 40% solution in toluene, 17.4 mmol, 1.2eq). The reaction was stirred for 2 minutes then added to a solution ofcompound 16 (assume 14.3 mmol, 1 eq) in THF (75 mL). After two hours, toa mixture of triphenyl phosphine (2.260 g, 8.62 mmol, 0.6 eq) in THF (20mL) was added DEAD (3.9 mL, 40% solution in toluene, 8.6 mmol, 0.6 eq).This was stirred for 2 minutes then added to the main reaction mixture.The reaction was stirred overnight then evaporated in vacuo. The residuewas chromatographed over silica gel with 0-50% EtOAc in hexanes. Theproduct fractions were evaporated in vacuo and the residue dried undervacuum at 30° C. to give the product 17 as a pale pink powder (2.239 g,7.88 mmol, 55% yield). ¹H NMR δ_(H) (400 MHz, DMSO-d₆) 7.95 (dd, J=8.8,5.5 Hz, 1H), 7.53 (d, J=3.5 Hz, 1H), 7.41 (d, J=3.5 Hz, 1H), 7.40-7.31(m, 2H), 4.58 (t, J=6.1 Hz, 2H), 3.33 (t, J=6.4 Hz, 2H). LC/MS, m/z=285[M+H]⁺ (Calc: 284).

Example 3 Synthesis of Compound 18

In a similar manner used to prepare compound 17, compound 18 wasprepared starting from methyl 2-(3-bromophenyl)acetate rather thanmethyl 2-(3-fluorophenyl)acetate. ¹H NMR δ_(H) (400 MHz, DMSO-d₆)7.82-7.75 (m, 2H), 7.68 (dd, J=8.6, 2.2 Hz, 1H), 7.53 (d, J=3.5 Hz, 1H),7.42 (d, J=3.7 Hz, 1H), 4.57 (t, J=6.1 Hz, 2H), 3.31 (t, J=6.1 Hz, 2H).LC/MS, m/z=345 [M+H]⁺ (Calc: 344).

Example 4 Synthesis of Compound 5

A mixture of compound 17 (0.143 g, 0.503 mmol, 1 eq),3H-spiro[isobenzofuran-1,4′-piperidine]hydrochloride (0.127 g, 0.563mmol, 1.1 eq), and iPr₂NEt (0.19 mL, 1.09 mmol, 2.2 eq) in acetonitrile(5 mL) was heated in a sealed pressure reaction bottle at 100° C. for 4days. The reaction was approximately half converted at this point. Thereaction was concentrated in vacuo and the residue chromatographed oversilica gel with 20-50% EtOAc in hexanes. The product fractions wereevaporated in vacuo. The residue was triturated with hexanes and hexanescontaining a small amount of EtOAc, then dried under vacuum at 40° C. togive compound 5 as a cream-colored powder (0.064 g, 0.14 mmol, 28%yield). ¹H NMR δ_(H) (400 MHz, DMSO-d₆) 7.60 (d, J=9.0 Hz, 1H), 7.50 (d,J=3.5 Hz, 1H), 7.35 (d, J=3.5 Hz, 1H), 7.31-7.21 (m, 4H), 7.02 (dd,J=6.4, 2.6 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 5.03 (s, 2H), 4.55 (t, J=6.4Hz, 2H), 3.94-3.86 (m, 2H), 3.26-3.16 (m, 4H), 1.93 (dt, J=12.9, 4.2 Hz,2H), 1.68 (d, J=12.7 Hz, 2H). LC/MS, m/z=454 [M+H]⁺ (Calc: 453).

Example 5 Synthesis of Compound 4

A mixture of compound 12 (0.136 g, 0.503 mmol, 1 eq),3H-spiro[isobenzofuran-1,4′-piperidine]hydrochloride (0.128 g, 0.567mmol, 1.1 eq), and iPr₂NEt (0.19 mL, 1.09 mmol, 2.2 eq) in acetonitrile(5 mL) were heated in a sealed pressure reaction bottle at 100° C. for 4days. The reaction was approximately half converted at this point. Thereaction was concentrated in vacuo and the residue chromatographed oversilica gel with 25-75% acetone in hexanes. The product fractions wereevaporated in vacuo. The residue was triturated with hexanes, filtered,then dried under vacuum at 40° C. to give compound 4 as a cream-coloredpowder (0.043 g, 0.10 mmol, 19% yield). ¹H NMR δ_(H) (400 MHz, DMSO-d₆)7.58 (d, J=9.0 Hz, 1H), 7.32-7.24 (m, 4H), 7.24-7.19 (m, 2H), 7.09 (dd,J=8.8, 2.4 Hz, 1H), 6.89 (d, J=4.8 Hz, 1H), 5.54 (s, 2H), 5.04 (s, 2H),3.94-3.86 (m, 2H), 3.25 (dt, J=12.7, 2.2 Hz, 2H), 1.98 (dt, J=12.9, 4.4Hz, 2H), 1.71 (d, J=12.5 Hz, 2H). LC/MS, m/z=440 [M+H]⁺ (Calc: 439).

Example 6 Synthesis of Compound 1

To a mixture of compound 12 (0.273 g, 1.01 mmol, 1 eq) in DMSO (2.0 mL)in a pressure reaction tube was added2-(pyridazin-4-yl)-4-(trifluoromethyl)phenol (0.243 g, 1.01 mmol, 1 eq)and K₂CO₃ (0.280 g, 2.03 mmol, 2 eq). The reaction mixture was heated at100° C. overnight then at 150° C. for 4 hours. When cooled, the reactionmixture was directly chromatographed over silica gel with 0-100% acetonein hexanes. The fractions containing the product were evaporated invacuo and the residue purified a once more by reverse-phasechromatography (C18, acetonitrile/water with 0.1% TFA, 20-90%). Theproduct fractions were frozen and lyophilized to yield compound 1 as ayellow-tan powder (0.007 g, 0.014 mmol, 1% yield). ¹H NMR δ_(H) (400MHz, DMSO-d₆) 9.49-9.47 (m, 1H), 9.29 (dd, J=5.3, 1.3 Hz, 1H), 8.14 (d,J=2.2 Hz, 1H), 7.96-7.90 (m, 2H), 7.82 (d, J=8.6 Hz, 1H), 7.43 (d, J=8.6Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.33 (dd, J=8.6, 2.6 Hz, 1H), 7.22 (d,J=4.8 Hz, 1H), 6.95 (d, J=4.6 Hz, 1H), 5.60 (s, 2H). LC/MS, m/z=491[M+H]⁺ (Calc: 490).

Example 7 Synthesis of Compound 2

To a mixture of compound 12 (0.100 g, 0.370 mmol, 1 eq) in NMP (3.5 mL)in a pressure reaction tube was added [1,1′-biphenyl]-2-ol (0.096 g,0.564 mmol, 1.5 eq) and K₂CO₃ (0.078 g, 0.564 mmol, 1.5 eq). Thereaction mixture was heated at 100° C. for 3 days. When cooled, thereaction mixture was diluted with 75 mL brine and extracted three timeswith 25 mL EtOAc. The organics were dried over MgSO₄, filtered andconcentrated in vacuo. The residue was chromatographed over silica gelwith 50-100% EtOAc in hexanes. The product fractions were evaporated invacuo then dried under vacuum at 40° C. to give compound 2 as acream-colored powder (0.120 g, 0.285 mmol, 77% yield). ¹H NMR δ_(H) (400MHz, DMSO-d₆) 7.70 (d, J=8.6 Hz, 1H), 7.54 (dd, J=7.5, 1.8 Hz, 1H),7.50-7.37 (m, 4H), 7.36-7.30 (m, 2H), 7.29-7.22 (m, 3H), 7.12 (d, J=2.4Hz, 1H), 7.02 (dd, J=8.6, 2.4 Hz, 1H), 6.93 (d, J=4.8 Hz, 1H), 5.55 (s,2H). LC/MS, m/z=421 [M+H]⁺ (Calc: 420).

Example 8 Synthesis of Compound 6

To a mixture of compound 18 (0.173 g, 0.501 mmol, 1 eq), sodium[1,1′-biphenyl]-2-olate (0.106 g, 0.552 mmol, 1.1 eq), Pd(dba)₂ (0.015g, 0.026 mmol, 0.05 eq), and Q-Phos (0.037 g, 0.052 mmol, 0.1 eq) in apressure reaction tube was added toluene (2.5 mL). The reaction wasstirred at ambient temperature for 2 hours, heated at 40° C. overnight,heated at 50° C. for 2 hours, the heated at 70° C. overnight. Thereaction mixture was evaporated in vacuo and the residue chromatographedover silica gel with 0-40% EtOAc in hexanes. The product fractions wereevaporated in vacuo. The residue thus obtained was repeatedly extractedwith warm hexanes and the pooled hexane extracts were concentrated tonear dryness. Additional fresh hexanes was added to bring the volume to˜1-2 mL. The solids were filtered off, rinsed with 1 mL of hexanes anddried under vacuum at 40° C. to give compound 6 as a light tancrystalline powder (0.066 g, 0.152 mmol, 30% yield. ¹H NMR δ_(H) (400MHz, DMSO-d₆) 7.76 (d, J=8.8 Hz, 1H), 7.56-7.49 (m, 2H), 7.49-7.41 (m,3H), 7.41-7.32 (m, 4H), 7.31-7.25 (m, 1H), 7.18 (dd, J=7.9, 1.1 Hz, 1H),6.91 (d, J=2.4 Hz, 1H), 6.87 (dd, J=8.8, 2.4 Hz, 1H), 4.53 (t, J=6.1 Hz,2H), 3.20 (t, J=6.1 Hz, 2H). LC/MS, m/z=435 [M+H]⁺ (Calc: 434).

Example 9 Synthesis of Compound 3

To a mixture of compound 12 (0.201 g, 0.744 mmol, 1 eq) in NMP (7.0 mL)in a pressure reaction tube was added 2-bromo-4-chlorophenol (0.233 g,1.12 mmol, 1.5 eq) and K₂CO₃ (0.153 g, 1.11 mmol, 1.5 eq). The reactionwas heated at 100° C. for 5 days. When cooled, the reaction mixture wasdiluted with 75 mL brine and extracted three times with 25 mL EtOAc. Thecombined organics were washed once with 25 mL brine, dried over Na₂SO₄,filtered and evaporated in vacuo. The residue was chromatographed oversilica gel with 30-100% EtOAc in hexanes. The product fractions wereevaporated in vacuo to give compound 19 as an off-white solid (0.122 g,0.267 mmol, 36% yield). LC/MS, m/z=457 [M+H]⁺ (Calc: 456).

To a mixture of compound 19 (0.122 g, 0.267 mmol, 1 eq) in dioxane (5.0mL) was added1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.065 g, 0.312 mmol, 1.2 eq), 2M Na₂CO₃ solution (0.27 mL, 0.54 mmol, 2eq) and PdCl₂(dppf) (0.016 g, 0.020 mmol, 0.07 eq). The reaction washeated at reflux overnight. When cooled, the reaction mixture waspartitioned between 25 mL EtOAc and 25 mL brine. The organics wereisolated, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was chromatographed over silica gel with 25-75% acetone inhexanes. The product fractions were evaporated in vacuo to give compound3 as a light tan powder (0.095 g, 0.21 mmol, 78% yield). ¹H NMR δ_(H)(400 MHz, DMSO-d₆) 7.70 (d, J=8.6 Hz, 1H), 7.67-7.61 (m, 2H), 7.36 (d,J=8.6 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.20 (d, J=4.8 Hz, 1H), 7.13-7.07(m, 2H), 6.93 (d, J=4.8 Hz, 1H), 6.24 (d, J=2.0 Hz, 1H), 5.55 (s, 2H),3.70 (s, 3H). LC/MS, m/z=459 [M+H]⁺ (Calc: 458).

Example 10 Synthesis of Compound 7

Compound 20 (11.467 g, 50.06 mmol, 1 eq) was cooled on an ice-salt bath.To this was added chlorosulfonic acid (30 mL, 450 mmol, 9 eq) dropwiseover ˜50 minutes. The ice bath was allowed to melt and the reactionwarmed up and stirred for 4 days. The reaction mixture was thencarefully poured onto ˜500 g ice chips. The resulting solid wascollected by filtration and rinsed with additional water. The solid waspartially air-dried then dissolved in 100 mL DCM, dried with MgSO₄,filtered and evaporated in vacuo to give compound 21 as a yellow-tansolid (12.446 g, 37.99 mmol, 76% yield). LC/MS, m/z=327 [M+H]⁺ (Calc:326).

To a mixture of compound 21 (12.446 g, 37.99 mmol, 1 eq) and2-aminothiazole (7.609 g, 76.98 mmol, 2 eq) was added 1:1 pyridine/DCM(100 mL). The mixture was heated at reflux for 3 hours then evaporatedin vacuo. The residue was partitioned between 50 mL EtOAc and 50 mL 1NHCl which caused a solid to form. The solid was collected via filtrationand washed once with 10 mL EtOAc and once with 25 mL water then oncemore with 10 mL EtOAc. The material was dried under vacuum at 40° C. togive compound 22 as a tan powder (3.437 g, 8.78 mmol, 23% yield). LC/MS,m/z=391 [M+H]⁺ (Calc: 390).

To a mixture of compound 22 (0.392 g, 1.00 mmol, 1 eq) in dioxane (5.0mL) in a pressure reaction tube was added4,4,5,5-tetramethyl-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,3,2-dioxaborolane(0.406 g, 1.11 mmol, 1.1 eq), 2N Na₂CO₃ solution (1.0 mL, 2.0 mmol, 2eq), and PdCl₂(dppf) (0.044 g, 0.054 mmol, 0.05 eq). The reaction wassealed and heated at 80° C. overnight. After cooling, the reactionmixture was diluted into 30 mL 10% citric acid solution and extractedonce with 50 mL DCM. The organics were dried over Na₂SO₄, filtered andevaporated in vacuo to give compound 23 which was carried on as-is.LC/MS, m/z=549 [M+H]⁺ (Calc: 548).

To a solution of compound 23 (assume 1.00 mmol) in THF (25 mL) was addedNaBH₄ (0.269 g, 7.11 mmol) and MeOH (2.5 mL). The reaction mixture washeated at reflux for 4 hours then additional NaBH₄ (1.007 g, 26.62 mmol)was added. After refluxing overnight, additional NaBH₄ (0.989 g, 26.14mmol) and MeOH (2.5 mL) were added. After 1 hour, more MeOH (2.5 mL) wasadded. After an additional hour more, MeOH (2.5 mL) was added. After 4hours, more NaBH₄ (1.007 g, 26.62 mmol) and MeOH (2.5 mL) were added.After refluxing one more night, the reaction was cooled. After coolingto ambient temperature the reaction mixture was diluted into 100 mL 10%citric acid solution, 25 mL brine was added and the mixture extractedwith 100 mL EtOAc. The organics were isolated and washed once with 25 mLbrine. The organics were dried over Na₂SO₄, filtered and evaporated invacuo to give compound 24 which was carried on as-is. LC/MS, m/z=521[M+H]⁺ (Calc: 520).

To a mixture of triphenyl phosphine (0.315 g, 1.20 mmol, 1.2 eq) in THF(5.0 mL) was added DEAD (0.55 mL, 40% solution in toluene, 1.21 mmol,1.2 eq). The reaction was stirred for 2 minutes then added to a solutionof compound 24 (assume 1.00 mmol, 1 eq) in THF (10.0 mL). After 1.5hours, to a mixture of triphenyl phosphine (0.159 g, 0.61 mmol, 0.6 eq)in THF (2.0 mL) was added DEAD (0.28 mL, 40% solution in toluene, 0.62mmol, 0.6 eq). This was stirred for 1 minute then added to the mainreaction mixture. The reaction was stirred for 30 minutes thenevaporated in vacuo. The residue was chromatographed over silica gelwith 0-40% EtOAc in hexanes. The product fractions were evaporated invacuo and the residue dried under vacuum at 50° C. to give compound 7 asan off-white glassy solid (0.160 g, 0.318 mmol, 32% yield). ¹H NMR δ_(H)(400 MHz, DMSO-d₆) 7.92 (d, J=8.8 Hz, 1H), 7.84-7.74 (m, 6H), 7.54 (d,J=3.5 Hz, 1H), 7.40 (d, J=3.7 Hz, 1H), 7.28-7.19 (m, 4H), 4.64 (t, J=6.1Hz, 2H), 3.39 (t, J=6.1 Hz, 2H). LC/MS, m/z=503 [M+H]⁺ (Calc: 502).

Example 10 Biological Testing

Representative Compounds of the Invention have been tested in theFLIPR®, FLIPR^(TETRA)®, and/or electrophysiology (EP) assays for sodiumchannel blocking activity, which is described in detail above.Representative values are presented in TABLE 4.

TABLE 4 Evaluation of compounds as sodium channel (Na_(v)) blockersCompound Na_(v)1.7 Example FLIPR assay No. IC₅₀ (μM) 1 1.741 2 >20 39.102 4 1.384 5 0.766 6 1.704 7 7.088

Having now fully described this disclosure, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the disclosure or anyembodiment thereof

Other embodiments of the disclosure will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents and publications cited herein are fully incorporated byreference in their entirety.

1. A compound having Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹ isoptionally substituted 5-membered heteroaryl; R² is selected from thegroup consisting of:

R^(3a) and R^(3b) are each independently selected from the groupconsisting of hydrogen and halogen; R^(4a), R^(4b), R^(4d), and R^(4e)are each independently selected from the group consisting of hydrogen,alkyl, halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy,carboxy, and alkoxycarbonyl; R^(4c) is selected from the groupconsisting of aryloxy and heteroaryloxy; R^(5a) is selected from thegroup consisting of optionally substituted aryl and optionallysubstituted heteroaryl; R^(5b), R^(5c), R^(5d), and R^(5e) are eachindependently selected from the group consisting of hydrogen, alkyl,halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, carboxy, andalkoxycarbonyl; R^(6a), R^(6b)R^(6c), and R^(6d) are each independentlyselected from the group consisting of hydrogen, alkyl, halo, nitro,cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, carboxy, andalkoxycarbonyl; and n is 1, 2, or
 3. 2. The compound of claim 1, whereinR^(3a) and R^(3b) are hydrogen, or a pharmaceutically acceptable salt orsolvate thereof.
 3. The compound of claim 1, wherein n is 1, or apharmaceutically acceptable salt or solvate thereof.
 4. The compound ofclaim 1, wherein n is 2, or a pharmaceutically acceptable salt orsolvate thereof.
 5. (canceled)
 6. The compound of claim 1, wherein R¹ isselected from the group consisting of optionally substitutedthiazol-2-yl and optionally substituted 1,3,4-thiadiazolyl, or apharmaceutically acceptable salt or solvate thereof.
 7. The compound ofclaim 6, wherein R¹ is optionally substituted 2-thiazolyl, or apharmaceutically acceptable salt or solvate thereof.
 8. (canceled) 9.The compound of claim 1, wherein: R² is:

R^(4c) is selected from the group consisting of aryloxy andheteroaryloxy; and R^(4a), R^(4b), R^(4d), and R^(4e) are eachindependently selected from the group consisting of hydrogen and halo,or a pharmaceutically acceptable salt or solvate thereof.
 10. Thecompound of claim 9, wherein R² is:

and R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each independentlyselected from the group consisting of hydrogen, alkyl, halo, nitro,cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, carboxy, andalkoxycarbonyl, or a pharmaceutically acceptable salt or solvatethereof.
 11. The compound of claim 1, wherein: R² is:

and R^(5b), R^(5c), R^(5d), and R^(5e) are each independently selectedfrom the group consisting of hydrogen, alkyl, halo, cyano, hydroxy,alkoxy, and haloalkoxy, or a pharmaceutically acceptable salt or solvatethereof.
 12. The compound of claim 11, wherein R^(5a) is optionallysubstituted phenyl, or a pharmaceutically acceptable salt or solvatethereof.
 13. (canceled)
 14. The compound of claim 1, wherein R² is:

or a pharmaceutically acceptable salt or solvate thereof.
 15. Thecompound of claim 14, wherein R^(6a), R^(6b), R^(6c), and R^(6d) areeach hydrogen, or a pharmaceutically acceptable salt or solvate thereof.16. The compound of claim 1 selected from the group consisting of:5-(2-(pyridazin-4-yl)-4-(trifluoromethyl)phenoxy)-2-(thiazol-2-yl)-2,3-dihydrobenzo-[d]isothiazole1,1-dioxide;5-([1,1′-biphenyl]-2-yloxy)-2-(thiazol-2-yl)-2,3-dihydrobenzo[d]isothiazole1,1-dioxide;5-(4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)-2-(thiazol-2-yl)-2,3-dihydrobenzo-[d]isothiazole1,1-dioxide;5-(3H-spiro[isobenzofuran-1,4′-piperidin]-1′-yl)-2-(thiazol-2-yl)-2,3-dihydrobenzo[d]isothiazole1,1-dioxide;6-(3H-spiro[isobenzofuran-1,4′-piperidin]-1′-yl)-2-(thiazol-2-yl)-3,4-dihydro-2H-benzo[e][1,2]thiazine1,1-dioxide;6-([1,1′-biphenyl]-2-yloxy)-2-(thiazol-2-yl)-3,4-dihydro-2H-benzo[e][1,2]thiazine1,1-dioxide; and2-(thiazol-2-yl)-6-(4-(4-(trifluoromethyl)phenoxy)phenyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine1,1-dioxide, or a pharmaceutically acceptable salt or solvate thereof17. A pharmaceutical composition comprising the compound of claim 1, ora pharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier.
 18. A method of treating a disorderresponsive to the blockade of sodium channels in a mammal, comprisingadministering to a mammal in need of such treatment an effective amountof a compound as claimed in claim 1, or a pharmaceutically acceptablesalt or solvate thereof. 19-20. (canceled)
 21. The method of claim 18,wherein a disorder responsive to the blockade of Na_(v)1.7 sodiumchannels is treated.
 22. A method of treating pain in a mammal,comprising administering an effective amount of a compound as claimed inclaim 1, or a pharmaceutically acceptable salt or solvate thereof, to amammal in need of such treatment.
 23. (canceled)
 24. The method of claim22, wherein said method is for preemptive or palliative treatment ofpain.
 25. The method of claim 22, wherein said pain is selected from thegroup consisting of chronic pain, inflammatory pain, neuropathic pain,acute pain, and surgical pain.
 26. A method of modulating Na_(v)1.7sodium channels in a mammal, comprising administering to the mammal amodulating-effective amount of at least one compound as claimed in claim1, or a pharmaceutically acceptable salt or solvate thereof. 27-29.(canceled)
 30. The compound as claimed in claim 1, wherein said compoundis ³H, ¹¹C, or ¹⁴C radiolabeled, or a pharmaceutically acceptable saltor solvate thereof. 31-40. (canceled)